The present invention relates to a compound of formula (I), (XI), (XII), (XIII), (XIV), (XV) or (XVI) and a derivative of a compound of formula (Ia) which have excellent antibiotic activity or a pharmaceutically acceptable salt thereof.
The present invention is also a pharmaceutical composition comprising a compound described above as an active ingredient effective to treat or prevent infectious diseases.
The present invention includes a use of a compound described above in order to prepare a medicament effective to treat or prevent infectious diseases.
The present invention is concerned with a method effective to treat or prevent infectious diseases in warm-blooded animals comprising administering a pharmacologically effective amount of a compound described above to them.
The present invention includes a microorganism capable of producing a compound of formula (I), (XI), (XII), (XIV), (XV) or (XVI).
The present invention also includes a process for preparing a compound of formula (I), (XI), (XII), (XIV), (XV) or (XVI) using the said microorganism.
A xcex2-lactam antibiotic, an amino-glycoside, isoniazid or rifampicin has been conventionally used in treatment or prophylaxis of microbial infections including tubercule bacillus. Recently there have been a lot of bacteria resistant to these antibiotics. It is desirable to develop new compounds which are different type antimicrobial agents from conventional ones.
On the other hand it has been known that capuramycin having a formula shown below exhibits anti-tubercule bacillus activity (J. Antibiotics. 29. (8). 1047-1053 (1986)). 
We found new compounds of formula (I), (XI), (XII), (XIV), (XV) or (XVI). which do not show any cross resistance to conventional medicaments, in the cultivation products of a microorganism. We prepared the derivatives of compounds described above and capuramycin. We studied the physiological activity of these derivatives for several years and found that these derivatives exhibit excellent antibiotic activity.
The compounds of the present invention can provide a method effective to treat and prevent infection diseases including ones arising from bacteria resistant to the conventional antibiotics. Compounds of formula (I), (XI), (XII), (XIV), (XV) or (XVI) are also useful starting materials for preparation of the compounds of the present invention having excellent antibiotic activity.
The present invention includes a compound of formula (I) 
(wherein
R1 is a methyl group, R2 is a methyl group, R4 is a hydroxy group, and X is a methylene group;
R1 is a methyl group, R2 is a hydrogen atom, R4 is a hydroxy group, and X is a methylene group;
R1 is a methyl group, R2 is a methyl group, R4 is a hydrogen atom, and X is a methylene group;
R1 is a hydrogen atom, R2 is a hydrogen atom, R4 is a hydroxy group, and X is a methylene group; or
R1 is a methyl group, R2 is a methyl group, R4 is a hydroxy group, and X is a sulfur atom) or a pharmaceutically acceptable salt thereof; or
a pharmaceutically acceptable ester, ether or N-alkylcarbamoyl derivative of a compound of formula (Ia) 
(wherein R1 is a hydrogen atom or a methyl group, R2a is a hydrogen atom, a protecting group for a hydroxy group, or a methyl group, R3 is a hydrogen atom or a protecting group for a hydroxy group, R4a is a hydrogen atom, a hydroxy group or a protected hydroxy group, R5 is a hydrogen atom or a protecting group for a hydroxy group, and X is a methylene group or a sulfur atom,
with the proviso that
when
X is a sulfur atom,
R1 is a methyl group, R2a is a methyl group, and R4a is a hydroxy group or a protected hydroxy group;
when
X is a methylene group, R1 is a methyl group, and R2a is a hydrogen atom,
R4a is a hydroxy group or a protected hydroxy group; or
when
X is a methylene group and R1 is a hydrogen atom,
R2a is a methyl group and R4a is a hydroxy group or protected hydroxy group);
or a pharmaceutically acceptable salt thereof.
the term xe2x80x9cN-alkylcarbamoylxe2x80x9d as used hereinafter in the specification includes N-alkylcarbamoyl, N-alkenylcarbamoyl and N-alkynylcarbamoyl.
The present invention is also a pharmaceutical composition comprising a compound described above as an active ingredient effective to treat or prevent infectious diseases.
The present invention includes the use of a compound described above in order to prepare a medicament effective to treat or prevent infectious diseases.
The present invention is concerned with a method effective to treat or prevent infectious diseases in warm-blooded animals comprising administering a pharmacologically effective amount of a compound described above to them.
The present invention includes a microorganism capable of producing a compound of formula (I).
The present invention also includes a process for preparing a compound of formula (I) using the said microorganism.
In the above formulae, the protecting group of xe2x80x9cprotecting group for a hydroxy groupxe2x80x9d and xe2x80x9cprotected hydroxy groupxe2x80x9d of R2a and the like can be removed by a chemical procedure such as hydrogenolysis, hydrolysis, electrolysis or photolysis (hereinafter referred to as a general protecting group) or can be removed by biological method such as hydrolysis in vivo (with the proviso that it is not an ester residue group such as an acyl group). xe2x80x9cThe protecting group which can be removed by biological method such as hydrolysis in vivoxe2x80x9d can be cleaved by biologically method such as hydrolysis in the human body to give a corresponding free acid or a salt thereof. Whether a compound has a protecting group removed in vivo is determined by detection of a corresponding parent compound or a pharmaceutically acceptable salt thereof in the body fluid of a rat or mouse to which it is administered by intravenous injection.
A general protecting group is selected from the group consisting of:
xe2x80x9ctetrahydropyranyl and tetrahydrothiopyranyl groupxe2x80x9d such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl;
xe2x80x9ctetrahydrofuranyl and tetrahydrothiofuranyl groupxe2x80x9d such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl;
xe2x80x9ctri(lower alkyl)silyl group (hereinafter a lower alkyl moiety represents a group selected from the group consisting of C1-C6 alkyl group such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl group) such as the trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, diisopropylmethylsilyl, di(tert-butyl)methylsilyl and triisopropylsilyl group;
xe2x80x9csilyl group substituted with one or two aryl groups and two or one lower alkyl groupsxe2x80x9d such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, and diisopropylphenylsilyl;
xe2x80x9clower alkoxymethyl groupxe2x80x9d (hereinafter an alkoxy moiety represents a group selected from the group consisting of C1-C6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy), such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and tert-butoxymethyl;
xe2x80x9clower alkoxy-lower alkoxylmethyl groupxe2x80x9d such as the 2-methoxyethoxymethyl group;
xe2x80x9chalogeno-lower-alkoxymethyl groupxe2x80x9d such as the 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl group;
xe2x80x9csubstituted ethyl groupxe2x80x9d, for example an ethyl group substituted with a lower alkoxy group such as the 1-ethoxyethyl or 1-(isopropoxy)ethyl group, and for example a halogenoethyl group such as the 2,2,2-trichloroethyl group;
xe2x80x9caralkyl groupxe2x80x9d (aryl moiety is selected from the group consisting of C6-C14 aryl group such as phenyl, naphthyl, biphenyl, anthryl and phenanthryl group), for example a lower alkyl group substituted with 1 to 3 aryl groups such as benzyl, xcex1-naphthyl, xcex2-naphthyl, diphenylmethyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl and 9-anthrylmethyl, and for example a lower alkyl group substituted with 1 to 3 aryl groups, which are substituted with lower alkyl, lower alkoxy, nitro, halogen or cyano group, such as the 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl group;
xe2x80x9calkoxycarbonyl groupxe2x80x9d, for example lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and isobutoxycarbonyl, and for example lower alkoxycarbonyl group substituted with halogen or tri(lower alkyl)silyl group such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl;
xe2x80x9calkenyloxycarbonyl groupxe2x80x9d (said alkenyl moiety is a C2-C6 alkenyl group) such as the vinyloxycarbonyl and allyloxycarbonyl group; and
xe2x80x9caralkyloxycarbonyl group in which the aryl ring is optionally substituted with one or two lower alkoxy or nitro groupsxe2x80x9d such as the benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl group.
A preferable xe2x80x9cgeneral protecting group of hydroxy groupxe2x80x9d is the tetrahydropyranyl, tetrahydrothiopyranyl, silyl, aralkyl or aralkyloxycarbonyl group.
A more preferable xe2x80x9cgeneral protecting group of hydroxy groupxe2x80x9d is the tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, di(tert-butyl)methylsilyl, diphenylmethylsilyl, benzyl, diphenylmethyl, triphenylmethyl, 4-methylbenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonyl group.
A most preferable xe2x80x9cgeneral protecting group of hydroxy groupxe2x80x9d is the trimethylsilyl, tert-butyldimethylsilyl, triphenylmethyl, benzyl or 4-methoxybenzyl group.
A hydroxy protecting group which can be removed by biological method such as hydrolysis in vivo is selected from the group consisting of
xe2x80x9c1-aliphatic acyloxy-lower alkyl groupxe2x80x9d (hereinafter, acyl moiety is selected from the group consisting of C1-C10 straight or branched chain alkanoyl group) such as formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pivaloyloxyhexyl;
xe2x80x9c1-(aliphatic-acylthio)-(lower alkyl)groupxe2x80x9d such as formylthiomethyl, acetylthiomethyl, dimethylaminoacetylthiomethyl, propionylthiomethyl, butyrylthiomethyl, pivaloylthiomethyl, valerylthiomethyl, isovalerylthiomethyl, hexanoylthiomethyl, 1-formylthioethyl, 1-acetylthioethyl, 1-propionylthioethyl, 1-butyrylthioethyl, 1-pivaloylthioethyl, 1-valerylthioethyl, 1-isovalerylthioethyl, 1-hexanoylthioethyl, 1-formylthiopropyl, 1-acetylthiopropyl, 1-propionylthiopropyl, 1-butyrylthiopropyl, 1-pivaloylthiopropyl, 1-valerylthiopropyl, 1-isovalerylthiopropyl, 1-hexanoylthiopropyl, 1-acetylthiobutyl, 1-propionylthiobutyl, 1-butyrylthiobutyl, 1-pivaloylthiobutyl, 1-acetylthiopentyl, 1-propionylthiopentyl, 1-butyrylthiopentyl, 1-pivaloylthiopentyl and 1-pivaloylthiohexyl;
xe2x80x9c1-(cycloalkylcarbonyloxy)-(lower alkyl) groupxe2x80x9d such as the cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl and 1-cyclohexylcarbonyloxybutyl group,
xe2x80x9c(1-aromatic acyloxy)-(lower alkyl) group (the aromatic acyl moiety is selected from the group consisting of C6-C10 arylcarbonyl groups)xe2x80x9d such as the benzoyloxymethyl group;
xe2x80x9c1-(lower alkoxycarbonyloxy)-(lower alkyl) groupxe2x80x9d such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(tert-butoxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(hexyloxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)propyl, 1-(pentyloxycarbonyloxy)propyl, 1-(hexyloxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)butyl, 1-(propoxycarbonyloxy)butyl, 1-(isopropoxycarbonyloxy)butyl, 1-(butoxycarbonyloxy)butyl, 1-(iosobutoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl and 1-(ethoxycarbonyloxy)hexyl;
xe2x80x9c1-(cycloalkyloxycarbonyloxy)-(lower alkyl) groupxe2x80x9d such as cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclopentyloxycarbonyloxy)pentyl, (cyclopentyloxycarbonyloxy)pentyl, 1-(cyclohexyloxycarbonyloxy)pentyl, 1-(cyclopentyloxycarbonyloxy)hexyl and 1-(cyclohexyloxycarbonyloxy)hexyl;
xe2x80x9cphthalidyl groupxe2x80x9d such as the phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl group;
xe2x80x9coxodioxolenylmethyl groupxe2x80x9d such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen4-yl )methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl )methyl and (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl;
xe2x80x9ccarbamoyl groupxe2x80x9d;
xe2x80x9ccarbamoyl group substituted with one or two lower alkyl groupsxe2x80x9d;
xe2x80x9clower alkyl-dithioethyl groupxe2x80x9d such as methyldithioethyl, ethyldithioethyl, propyldithioethyl, butyldithioethyl, pentyldithioethyl and hexyldithioethyl group; and
xe2x80x9c1-(acyloxy)alkyloxycarbonyl groupxe2x80x9d such as the pivaloyloxymethyloxycarbonyl group.
A preferable xe2x80x9chydroxy protecting group which can be removed by biological method such as hydrolysis in vivoxe2x80x9d is selected from the group consisting of a 1-(aliphatic acyloxy)-(lower alkyl) group, a 1-(cycloalkylcarbonyloxy)-(lower alkyl) group, a 1-(lower alkoxycarbonyloxy)-(lower alkyl) group, a 1-(cycloalkyloxycarbonyloxy)-(lower alkyl) group, a phthalidyl and an oxodioxolenylmethyl group.
A more preferable xe2x80x9chydroxy protecting group which can be removed by biological method such as hydrolysis in vivoxe2x80x9d is selected from the group consisting of acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, 1-acetoxyethyl, butyryloxyethyl, 1-pivaloyloxyethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl, cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, phthalidyl, (5-phenyl-2-oxo-1,3-dioxolen4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl group.
A most preferable xe2x80x9chydroxy protecting group which can be removed by biological method such as hydrolysis in vivoxe2x80x9d is selected from the group consisting of acetoxymethyl, propionyloxymethyl, butyrvloxymethyl, pivaloyloxymethyl, valeryloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyioxymethyl, isobutoxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, (5-phenyl-2-oxo-1,3-dioxolen-4-yl )methyl. [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-ethyl-2-oxo-1,3-dioxolen-4-yl )methyl group.
The term xe2x80x9cpharmaceutically acceptable ester, ether and N-alkylcarbamoyl derivativesxe2x80x9d refers to a derivative that is a useful medicament without significant toxicity.
The ester residue of ester derivatives is selected from the group consisting of xe2x80x9ccarbonyl and oxycarbonyl group to which a straight or branched chain C1-C21 alkyl group is attachedxe2x80x9d, in which said alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl. 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, icosyl, 3,7,11,15-tetramethylhexadecyl and henicosyl groups;
xe2x80x9ccarbonyl and oxycarbonyl group to which a straight or branched chain C2-C21 alkenyl or alkynyl group is attachedxe2x80x9d, in which said alkenyl or alkynyl group is selected from the group consisting of ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, cis-8-heptadecenyl, cis, cis-8,11-heptadecadienyl, cis, cis, cis-8,11,14-heptadecatrienyl, cis-10-nonadecenyl, and cis-12-icosenyl;
xe2x80x9ccarbonyl and oxycarbonyl group to which a straight or branched chain C2-C21 alkenyl or alkynyl group is attachedxe2x80x9d, in which said alkenyl or alkynyl group is selected from the group consisting of ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl;
xe2x80x9ccarbonyl and oxycarbonyl group to which straight or branched chain C1-C21, alkyl group which has one or more substituents selected from the group consisting of lower alkoxy, halogen (hereinafter for example fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine) and nitro groups is attachedxe2x80x9d, in which said substituted alkyl group is selected from the group consisting of methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, 2,2-dibromoethyl, nitromethyl, dinitromethyl, 1-nitroethyl, 2-nitroethyl and 1,2-dinitroethyl;
xe2x80x9ccarbonyl and oxycarbonyl group to which a (C6-C10 aryl)-(C1-C21) alkyl group wherein said aryl moiety optionally has one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groups is attachedxe2x80x9d, in which said arylalkyl group is selected from the group consisting of benzyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl, indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthvlbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl and 6-naphthylhexyl;
xe2x80x9ccarbonyl and oxycarbonyl group to which a C6-C10 aryl group which optionally has one or more substituents selected from the group consisting of lower alkyl, lower alkoxy halo and nitro groups is attachedxe2x80x9d, in which said aryl group is selected from the group consisting of phenyl, naphthyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,5-dibromophenyl, 2,5-dibromophenyl 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,3,6-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 2,5,6-trifluorophenyl, 2,4,6-trifluorophenyl, 2,3,6-tribromophenyl, 2,3,4-tribromophenyl, 3,4,5-tribromophenyl, 2,5,6-trichlorophenyl, 2,4,6-trichlorophenyl, 1-fluoro-2-naphthyl, 2-fluoro-1-naphthyl, 3-fluoro-1-naphthyl, 1-chloro-2-naphthyl, 2-chloro-1-naphthyl, 3-bromo-1-naphthyl, 3,8-difluoro-1-naphthyl, 2,3-difluoro-1-naphthyl, 4,8-difluoro-1-naphthyl, 5,6-difluoro-1-naphthyl, 3,8-dichloro-1-naphthyl, 2,3-dichloro-1-naphthyl, 4,8-dibromo-1-naphthyl, 5,6-dibromo-1-naphthyl, 2,3,6-trifluoro-1-naphthyl, 2,3,4-trifluoro-1-naphthyl, 3,4,5-trifluoro-1-naphthyl, 4,5,6-trifluoro-1-naphthyl, 2,4,8-trifluoro-1-naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl, 3,5-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,4-dimethylphenyl, 3,5-dibutylphenyl, 2,5-dipentylphenyl, 2,6-dipropylmethylphenyl, 2,4-dipropylphenyl, 2,3,6-trimethylphenyl, 2,3,4-trimethylphenyl, 3,4,5-trimethylphenyl, 2,5,6-trimethylphenyl, 2,4,6-trimethylphenyl, 2,3,6-tributylphenyl, 2,3,4-tripentylphenyl, 3,4,5-tributylphenyl, 2,5,6-tripropylmethylphenyl, 2,4,6-tripropylphenyl, 1-methyl-2-naphthyl, 2-methyl-1-naphthyl, 3-methyl-1-naphthyl, 1-ethyl-2-naphthyl, 2-propyl-1-naphthyl, 3-butyl-1-naphthyl, 3,8-dimethyl-1-naphthyl, 2,3-dimethyl-1-naphthyl, 4,8-dimethyl-1-naphthyl, 5,6-dimethyl-1-naphthyl, 3,8-diethyl-1-naphthyl, 2,3-dipropyl-1-naphthyl, 4,8-dipentyl-1-naphthyl, 5,6-dibutyl-1-naphthyl, 2,3,6-trimethyl-1-naphthyl, 2,3,4-trimethyl-1-naphthyl, 3,4,5-trimethyl-1-naphthyl, 4,5,6-trimethyl-1-naphthyl, 2,4,8-trimethyl-1-naphthyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-propoxphenyl, 4-ethoxyphenyl, 2-butoxyphenyl, 3-pentyloxyphenyl, 4-pentyloxyphenyl, 3,5-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dibutoxyphenyl, 2,5-dipentyloxyphenyl, 2,6-dipropoxymethoxphenyl, 2,4-dipropoxyphenyl, 2,3,6-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 5,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,3,6-tributoxyphenyl, 2,3,4-tripentyloxyphenyl, 3,4,5-tributoxyphenyl, 2,5,6-tripropoxyphenyl, 2,4,6-tripropoxyphenyl, 1-methoxy-2-naphthyl, 2-methoxy-1-naphthyl, 3-methoxy-1-naphthyl, 1-ethoxy-2-naphthyl, 2-propoxy-1-naphthyl, 3-butoxy-1-naphthyl, 3,8-dimethoxy-1-naphthyl, 2,3-dimethoxy-1-naphthyl, 4,8-dimethoxy-1-naphthyl 5,6-dimethoxy-1-naphthyl, 3,8-diethoxy-1-naphthyl, 2,3-dipropoxy-1-naphthyl, 4,8-dipentyloxy-1-naphthyl, 5,6-dibutoxy-1-naphthyl, 2,3,6-trimethoxy-1-naphthyl, 2,3,4-trimethoxy-1-naphthyl, 3,4,5-trimethoxy-1-naphthyl, 4,5,6-trimethoxy-1-naphthyl, 2,4,8-trimethoxy-1-naphthyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-dinitrophenyl, 2,5-dinitrophenyl 2,6-dinitrophenyl, 2,4-dinitrophenyl, 2,3,6-trinitrophenyl, 2,3,4-trinitrophenyl, 3,4,5-trinitrophenyl, 2,5,6-trinitrophenyl, 2,4,6-trinitrophenyl, 1-nitro-2-naphthyl, 2-nitro-1-naphthyl, 3-nitro-1-naphthyl, 3,8-dinitro-1-naphthyl, 2,3-dinitro-1-naphthyl, 4,8-dinitro-1-naphthyl, 5.6-dinitro-1-naphthyl. 2,3,6-trinitro-1-naphthyl, 2,3,4-trinitro-1-naphthyl, 3,4,5-trinitro-1-naphthyl, 4,5,6-trinitro-1-naphthyl and 2,4,8-trinitro-1-naphthyl;
xe2x80x9ccarboxy (C1-C10)alkylcarbonyl groupxe2x80x9d such as succinoyl, glutaroyl, and adipoyl;
xe2x80x9cresidue of salt of a phosphate diester which independently has two lower alkyl groupsxe2x80x9d; and xe2x80x9cresidue forming ester of amino acid which is optionally protected with a tert-butyloxycarbonyl, benzyloxycarbonyl or trityl groupxe2x80x9d such as glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, glutamine and glutamic acid.
A preferable ester residue of ester derivatives is R6COxe2x80x94 or R6OCOxe2x80x94 group wherein R6 is selected from the group consisting of hydrogen; a C1-C21 alkyl group; a C2-C21 alkenyl or alkynyl group having 1 to 3 double or triple bonds; a C1-C21 alkyl group substituted with 1 to 4 substituents selected from the group consisting of lower alkoxy, halo and nitro groups; a C1-C21 alkyl group substituted with 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groups; and a C6-C10 aryl group which is optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo, and nitro groups.
A more preferable ester residue of ester derivatives is R6COxe2x80x94 or R6OCOxe2x80x94 group wherein R6 is selected from the group consisting of hydrogen; a C1-C21 alkyl group; a C2-C21 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group substituted with 1 to 4 substituents selected from the group consisting of C1-C4 alkoxy, halo and nitro groups; a C1-C6 alkyl group substituted with 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups; and a C6-C10 aryl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups.
A more preferable ester residue of ester derivatives is R6COxe2x80x94 or R6OCOxe2x80x94 group wherein R6 is selected from the group consisting of a C1-C21 alkyl group; a C6-C20 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group substituted with one substituent selected from the group consisting of C1-C4 alkoxy and nitro groups; a C1-C6 alkyl group substituted with 1 to 3 substituents selected from the group consisting of halogen; a C1-C4 alkyl group substituted with 1 to 3 phenyl or naphthyl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups; and a phenyl or naphthyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups.
A more preferable ester residue of ester derivatives is R6COxe2x80x94 or R6OCOxe2x80x94 group wherein R6 is selected from the group consisting of a C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group substituted with one substituent selected from the group consisting of C1-C4 alkoxy and nitro groups: a C1-C4 alkyl group substituted with 1 to 3 substituents selected from the group consisting of fluoro and chloro groups: a C1-C4 alkyl group substituted with 1 to 3 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups; and a phenyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
A more preferable ester residue of ester derivatives is R6COxe2x80x94 or R6OCOxe2x80x94 group wherein R6 is selected from the group consisting of a C6-C20 alkyl group, a C10-C20 alkenyl group having 1 to 3 double bonds, a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group substituted with one substituent selected from the group consisting of C1-C4 alkoxy, fluoro, chloro and nitro groups; a C1-C4 alkyl group substituted with 1 to 3 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups; and a phenyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C2 alkyl C1-C4 alkoxy, fluoro and chloro groups.
A still more preferable ester residue of ester derivatives is R6COxe2x80x94 or R6OCOxe2x80x94 group wherein R6 is selected from the group consisting of a C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group substituted with one substituent selected from the group consisting of C1-C4 alkoxy groups, and a C1-C4 alkyl group substituted with 1 or 2 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
A most preferable ester residue of ester derivatives is R6COxe2x80x94 or R6OCOxe2x80x94 group wherein R6 is selected from the group consisting of a C6-C20 alkyl group and a C10-C20 alkenyl group having 1 to 3 double bonds.
An ether residue of ether derivatives is selected from the group consisting of
xe2x80x9cstraight or branched chain C1-C21 alkyl groupxe2x80x9d such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, icosyl, 3,7,11,15-tetramethylhexadecyl and henicosyl groups;
xe2x80x9cstraight or branched chain C2-C21 alkenyl or alkynyl groupxe2x80x9d such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, cis-8-heptadecenyl, cis, cis-8,11-heptadecadienyl, cis, cis, cis-8,11,14-heptadecatrienyl, cis-10-nonadecenyl, cis-12-icosenyl, ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl;
xe2x80x9cstraight or branched chain C1-C21 alkyl group which has one or more substituents selected from the group consisting of lower alkoxy, halogen (hereinafter for example fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine) and nitro groupsxe2x80x9d such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethyl, tnchloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, 2,2-dibromoethyl, nitromethyl, dinitromethyl, 1-nitroethyl, 2-nitroethyl and 1,2-dinitroethyl;
xe2x80x9c(C6-C10)aryl-(C1-C21)alkyl group wherein said aryl moiety optionally has one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groupxe2x80x9d such as benzyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl, indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl. 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentvl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl and 6-naphthylhexyl; and
xe2x80x9cC6-C10aryl group which optionally has one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groupsxe2x80x9d such as phenyl, naphthyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,5-dibromophenyl, 2,5-dibromophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,3,6-trifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 2,5,6-trifluorophenyl, 2,4,6-trifluorophenyl, 2,3,6-tribromophenyl, 2,3,4-tribromophenyl, 3,4,5-tribromophenyl, 2,5,6-trichlorophenyl, 2,4,6-trichlorophenyl, 1-fluoro-2-naphthyl, 2-fluoro-1-naphthyl, 3-fluoro-1-naphthyl, 1-chloro-2-naphthyl, 2-chloro-1-naphthyl, 3-bromo-1-naphthyl, 3,8-difluoro-1-naphthyl, 2,3-difluoro-1-naphthyl, 4,8-difluoro-1-naphthyl, 5,6-difluoro-1-naphthyl, 3,8-dichloro-1-naphthyl, 2,3-dichloro-1-naphthyl, 4,8-dibromo-1-naphthyl, 5,6-dibromo-1-naphthyl, 2,3,6-trifluoro-1-naphthyl, 2,3,4-trifluoro-1-naphthyl, 3,4,5-trifluoro-1-naphthyl, 4,5,6-trifluoro-1-naphthyl, 2,4,8-trifluoro-1-naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl, 3,5-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,4-dimethylphenyl, 3,5-dibutylphenyl, 2,5-dipentylphenyl, 2,6-dipropylmethylphenyl, 2,4-dipropylphenyl, 2,3,6-trimethylphenyl, 2,3,4-trimethylphenyl, 3,4,5-trimethylphenyl, 2,5,6-trimethylphenyl, 2,4,6-trimethylphenyl, 2,3,6-tributyiphenyl, 2,3,4-tripentylphenyl, 3,4,5-tributylphenyl, 2,5,6-tripropylmethylphenyl, 2,4,6-tripropylphenyl, 1-methyl-2-naphthyl, 2-methyl-1-naphthyl, 3-methyl-1-naphthyl, 1-ethyl-2-naphthyl, 2-propyl-1-naphthyl, 3-butyl-1-naphthyl, 3,8-dimethyl-1-naphthyl, 2,3-dimethyl-1-naphthyl, 4,8-dimethyl-1-naphthyl, 5,6-dimethyl-1-naphthyl, 3,8-diethyl-1-naphthyl, 2,3-dipropyl-1-naphthyl, 4,8-dipentyl-1-naphthyl, 5,6-dibutyl-1-naphthyl, 2,3,6-trimethyl-1-naphthyl, 2,3,4-trimethyl-1-naphthyl, 3,4,5-trimethyl-1-naphthyl, 4,5,6-trimethyl-1-naphthyl, 2,4,8-trimethyl-1-naphthyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-propoxyphenyl, 4-ethoxyphenyl, 2-butoxyphenyl, 3-pentoxyphenyl, 4-pentyloxyphenyl, 3,5-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dibutoxyphenyl, 2,5-dipentyloxyphenyl, 2,6-dipropoxymethoxyphenyl, 2,4-dipropoxyphenyl, 2,3,6-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,5,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,3,6-tributoxyphenyl, 2,3,4-tripentyloxyphenyl, 3,4,5-tributoxyphenyl, 2,5,6-tripropoxyphenyl, 2,4,6-tripropoxyphenyl, 1-methoxy-2-naphthyl, 2-methoxy-1-naphthyl, 3-methoxy-1-naphthyl, 1-ethoxy-2-naphthyl, 2-propoxy-1-naphthyl, 3-butoxy-1-naphthyl, 3,8-dimethoxy-1-naphthyl, 2,3-dimethoxy-1-naphthyl, 4,8-dimethoxy-1-naphthyl, 5,6-dimethoxy-1-naphthyl, 3,8-diethoxy-1-naphthyl, 2,3-dipropoxy-1-naphthyl, 4,8-dipentyloxy-1-naphthyl, 5,6-dibutoxy-1-naphthyls 2,3,6-trimethoxy-1-naphthyl, 2,3,4-trimethoxy-1-naphthyl, 3,4,5-trimethoxy-1-naphthyl, 4,5,6-trimethoxy-1-naphthyl, 2,4,8-trimethoxy-1-naphthyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-dinitrophenyl, 2,5-dinitrophenyl, 2,6-dinitrophenyl, 2,4-dinitrophenyl, 2,3,6-trinitrophenyl, 2,3,4-trinitrophenyl, 3,4,5-trinitrophenyl, 2,5,6-trinitrophenyl, 2,4,6-trinitrophenyl, 1-nitro-2-naphthyl, 2-nitro-1-naphthyl, 3-nitro-1-naphthyl, 3,8-dinitro-1-naphthyl, 2,3-dinitro-1-naphthyl, 4,8-dinitro-1-naphthyl, 5,6-dinitro-1-naphthyl, 2,3,6-trinitro-1-naphthyl, 2,3,4-trinitro-1-naphthyl, 3,4,5-trinitro-1-naphthyl, 4,5,6-trinitro-1-naphthyl and 2,4,8-trinitro-1-naphthyl. A preferable ether residue of ether derivatives is selected from the group consisting of a C1-C21 alkyl group; a C2-C21 alkenyl or alkynyl group having 1 to 3 double or triple bonds; a C1-C2a alkyl group which has 1 to 4 substituents selected from the group consisting of lower alkoxy, halo and nitro groups; a C1-C21 alkyl group which has 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl. lower alkoxy, halo and nitro groups; and a C6-C10 aryl group which is optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groups.
A more preferable ether residue of ether derivatives is selected from the group consisting of a C1-C21 alkyl group; a C2-C21 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group which has 1 to 4 substituents selected from the group consisting of C1-C4 alkoxy, halogen and nitro groups; a C1-C6 alkyl group which has 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups; and a C6-C10 aryl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups.
A more preferable ether residue of ether derivatives is selected from the group consisting of a C1-C21 alkyl group; a C6-C20 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy and nitro groups; a C1-C6 alkyl group which has 1 to 3 substituents selected from the group consisting of halo groups; a C1-C4 alkyl group which has 1 to 3 phenyl or naphthyl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups; and a phenyl or naphthyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups.
A more preferable ether residue of ether derivatives is selected from the group consisting of a C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy and nitro group; a C1-C4 alkyl group which has 1 to 3 substituents selected from the group consisting of fluoro and chloro groups; a C1-C4 alkyl group which has 1 to 3 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro group; and a phenyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy. fluoro and chloro groups.
A more preferable ether residue of ether derivatives is selected from the group consisting of a C6-C20 alkyl group: a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy, fluoro, chloro and nitro groups; a C1-C4 alkyl group which has 1 to 3 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups; and a phenyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C2 alkyl, C1-C4alkoxy, fluoro and chloro groups.
A still more preferable ether residue of ether derivative is selected from the group consisting of a C6-C20 alkyl group: a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy groups; and a C1-C4 alkyl group which has 1 or 2 phenyl groups optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkydl C1-C4 alkoxy, fluoro and chloro groups.
A most preferable ether residue of ether derivatives is selected from the group consisting of a C6-C20 alkyl group and a C10-C20 alkenyl group having 1 to 3 double bonds.
An alkyl residue of N-alkylcarbamoyl derivatives is selected from the group consisting of
xe2x80x9cstraight or branched chain C1-C21 alkyl groupxe2x80x9d such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, icosyl, 3,7,11,15-tetramethylhexadecyl and henicosyl groups;
xe2x80x9cstraight or branched chain C2-C21 alkenyl or alkynyl groupxe2x80x9d such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, cis-8-heptadecenyl, cis, cis-8,11-heptadecadienyl, cis, cis, cis-8,11,14-heptadecatrienyl, cis-10-nonadecenyl, cis-12-icosenyl, ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl;
xe2x80x9cstraight or branched chain C1-C21 alkyl group which has substituents selected from the group consisting of alkoxy. halogen (hereinafter example fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine) and nitroxe2x80x9d such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, 2,2-dibromoethyl, nitromethyl, dinitromethyl, 1-nitroethyl, 2-nitroethyl and 1,2-dinitroethyl; and
xe2x80x9c(C6-C10)aryl-(C1-C21)alkyl group wherein said aryl moiety optionally has substituent selected from the group consisting of lower alkyl, lower alkoxy, halogen and nitro groupsxe2x80x9d such as benzyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl, indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl and 6-naphthylhexyl.
A preferable alkyl residue of N-alkylcarbamoyl derivatives is selected from the group consisting of a C1-C21 alkyl group; a C2-C21 alkenyl or alkynyl group having 1 to 3 double or triple bonds; a C1-C21 alkyl group which has one or more substituents selected from the group consisting of lower alkoxy, halo and nitro groups; and a C1-C21 alkyl group which has 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groups.
A more preferable alkyl residue of N-alkylcarbamoyl derivatives is selected from the group consisting of a C1-C21 alkyl group; a C2-C21 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group which has 1 to 4 substituents selected from the group consisting of C1-C4 alkoxy, halogen and nitro groups; and a C1-C6 alkyl group which has 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups.
A more preferable alkyl residue of N-alkylcarbamoyl derivatives is selected from the group consisting of a C1-C21 alkyl group; a C6-C20 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy and nitro groups; a C1-C6 alkyl group which has 1 to 3 substituents selected from the group consisting of halo group; and a C1-C4 alkyl group which has 1 to 3 phenyl or naphthyl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups.
A more preferable alkyl residue of N-alkylcarbamoyl derivatives is selected from the group consisting of a C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond: a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy and nitro groups; a C1-C4 alkyl group which has 1 to 3 substituents selected from the group consisting of fluoro and chloro groups; and a C1-C4 alkyl group which has 1 to 3 phenyl groups which are optionally substituted with 1 to 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
A more preferable alkyl residue of N-alkylcarbamoyl derivatives is selected from the group consisting of a C6-C10 alkyl group, a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy. fluoro, chloro and nitro groups, and a C1-C4 alkyl group which has 1 to 3 phenyl groups which are optionally substituted with 1 to 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
A still more preferable alkyl residue of N-alkylcarbamoyl derivative is selected from the group consisting of a C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy groups; and a C1-C4 alkyl group which has 1 to 2 phenyl groups optionally substituted with 1 to 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
A most preferable alkyl residue of N-alkylcarbamoyl derivatives is selected from the group consisting of a C6-C20 alkyl group and a C10-C20 alkenyl group having 1 to 3 double bonds.
In compound (Ia), there are several functional groups to which the hydroxy protecting group, and the ester, ether and alkyl residues can be attached. Therefore a plurality of protecting groups and residues can independently exist by optional combination of these protecting groups and residues.
A preferable pharmaceutically acceptable ester derivative of (Ia) is a derivative which has one or two of the ester residues at R2, R3 and/or R5. A more preferable ester derivative is a derivative which has one or two of the ester residues at R3 and/or R5. A still more preferable ester derivative is a derivative which has one of the ester residues at R3 or R5. A most preferable ester derivative is a derivative which has one of the ester residue at R3.
A preferable pharmaceutically acceptable ether derivative of (Ia) is a derivative which has one or two of the ether residues at R2, R3 and/or R5. A more preferable ether derivative is a derivative which has one or two of the ether residues at R3 and/or R5. A still more preferable ether derivative is a derivative which has one of the ether residues at R3 or R5. A most preferable ether derivative is a derivative which has one of the ether residues at R3.
A preferable pharmaceutically acceptable N-alkylcarbamoyl derivative is a derivative having one of the alkyl residues.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to a salt that is a useful medicament without significant toxicity.
Where compound (I), (Ia), and pharmaceutically acceptable ester, ether and N-alkyl derivatives of compound (Ia) have a basic group such as an amino group these compounds can be converted into an acid addition salt by a conventional treatment with an acid. Such acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, benzoate, oxalate. maleate, fumarate, tartrate and citrate; and sulfonic acid salts such as methanesulfonate, benzenesulfonate and p-toluenesulfonate.
Where compound (I) and pharmaceutically acceptable ester, ether and N-alkyl derivatives of compound (Ia) have an acidic group such as a carboxy group, these compounds can be converted into a base addition salt by a conventional treatment with a base. Such base addition salts include alkali metal salts such as sodium, potassium and lithium salts; alkaline earth metal salts such as calcium and magnesium salts; metal salts such as aluminium, iron, zinc, copper, nickel and cobalt salts; and quaternary ammonium salts such as ammonium salt.
When compound (I) and pharmaceutically acceptable derivative of compound (Ia) are allowed to stand in the atmosphere, these compounds may take up water to form a hydrate. The present invention includes such hydrates. Compound (I) and pharmaceutically acceptable derivative of compound (Ia) may absorb a solvent to form a solvate. The present invention includes such solvates.
Compound (I) and pharmaceutically acceptable derivative of compound (Ia) have several asymmetric carbons and therefore they can exist as several stereoisomers such as enantiomers and diastereomers in which each carbon has R or S configuration. The compound of the present invention encompasses individual enantiomers and diastereomers and mixtures of these stereoisomers in all proportions.
A preferable configuration of the compound of the present invention is shown below: 
A preferable compound (I) is selected from the following compounds:
(1) a compound (I) wherein R2 is a methyl group,
(2) a compound (I) wherein R4 is a hydroxy group,
(3) a compound (I) wherein X is a methylene group;
or a compound wherein R2, R4 and X is selected in optional combination of (1), (2) and (3), for example:
(4) a compound (I) wherein R4 is a hydroxy group and X is a methylene group, and
(5) a compound (I) wherein R2 is a methyl group, R4 is a hydroxy group and X is a methylene group.
A preferable compound of formula (Ia) is selected from the following compounds:
(i) a compound (Ia) wherein the protecting group for a hydroxy group is selected from the group consisting of xe2x80x9ctetrahydropyranyl or tetrahydrothiopyranyl groupxe2x80x9d, xe2x80x9csilyl groupxe2x80x9d, xe2x80x9caralkyl groupxe2x80x9d, xe2x80x9caralkyloxycarbonyl groupxe2x80x9d, xe2x80x9c1-(aliphatic acyloxy)-(lower alkyl) groupxe2x80x9d, xe2x80x9c1-(cycloalkylcarbonyloxy)-(lower alkyl) groupxe2x80x9d, xe2x80x9c1-(lower alkoxycarbonyloxy)-(lower alkyl) groupxe2x80x9d, xe2x80x9c1-(cycloalkyloxycarbonyloxy)-(lower alkyl) groupxe2x80x9d, xe2x80x9cphthalidylxe2x80x9d and xe2x80x9coxodioxolenylmethyl groupxe2x80x9d.
(ii) a compound (Ia) wherein the protecting group for a hydroxy group is selected from the group consisting of tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, di(tert-butyl)methylsilyl, diphenylmethylsilyl, benzyl, diphenylmethyl, triphenylmethyl, 4-methylbenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, 1-acetoxyethyl, butyryloxyethyl, 1-pivaloyloxyethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl, cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, phthalidyl, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl group.
(iii) a compound (Ia) wherein the protecting group of hydroxy group is selected from the group consisting of trimethylsilyl, tert-butyldimethylsilyl, triphenylmethyl, benzyl, 4-methoxybenzyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl group.
A preferable ester derivative of compound (Ia) is selected from the following compounds:
(iv) an ester derivative of compound (Ia) wherein the ester residue is R6COxe2x80x94 or R6OCOxe2x80x94 group in which R6 is selected from the group consisting of hydrogen; a C1-C21 alkyl group; a C2-C21 alkenyl or alkynyl group having 1 to 3 double or triple bonds; a C1-C21 alkyl group substituted with 1 to 4 substituents selected from the group consisting of lower alkoxy, halo and nitro groups; a C1-C21 alkyl group substituted with 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groups; and a C6-C10 aryl group which is optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groups.
(v) an ester derivative of compound (Ia) wherein the ester residue is R6COxe2x80x94 or R6OCOxe2x80x94 group in which R6 is selected from the group consisting of hydrogen; a C1-C21 alkyl group; a C2-C21 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group substituted with 1 to 4 substituents selected from the group consisting of C1-C4 alkoxy, halo and nitro groups; a C1-C6 alkyl group substituted with 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups; and a C6-C10 aryl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl C1-C4 alkoxy, halo and nitro groups.
(vi) an ester derivative of compound (Ia) wherein the ester residue is R6COxe2x80x94 or R6OCOxe2x80x94 group in which R6 is selected from the group consisting of a C1-C2, alkyl group; a C6-C20 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group substituted with one substituent selected from the group consisting of C1-C4 alkoxy and nitro groups; a C1-C6 alkyl group substituted with 1 to 3 substituents selected from the group consisting of halogen; a C1-C4 alkyl group substituted with 1 to 3 phenyl or naphthyl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups; and a phenyl or naphthyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups.
(vii) an ester derivative of compound (Ia) wherein the ester residue is R6COxe2x80x94 or R6OCOxe2x80x94 group in which R6 is selected from the group consisting of C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group substituted with one substituent selected from the group consisting of C1-C4 alkoxy, and nitro groups: a C1-C4 alkyl group substituted with 1 to 3 substituents selected from the group consisting of fluoro and chloro groups; a C1-C4 alkyl group substituted with 1 to 3 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro, and chloro groups; and a phenyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
(viii) an ester derivative of compound (Ia) wherein the ester residue is R6COxe2x80x94 or R6OCOxe2x80x94 group in which R6 is selected from the group consisting of a C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group substituted with one substituent selected from the group consisting of C1-C4 alkoxy, fluoro, chloro and nitro groups a C1-C4 alkyl group substituted with 1 to 3 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro, and chloro groups; and a phenyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
(ix) an ester derivative of compound (Ia) wherein the ester residue is R6COxe2x80x94 or R6OCOxe2x80x94 group in which R6 is selected from the group consisting of a C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group substituted with one substituent selected from the group consisting of C1-C4 alkoxy groups; and a C1-C4 alkyl group substituted with 1 to 2 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
(x) an ester derivative of compound (Ia) wherein the ester residue is R6COxe2x80x94 or R6OCOxe2x80x94 group in which R6 is selected from the group consisting of a C6-C20 alkyl group; and a C10-C20 alkenyl group having 1 to 3 double bonds.
A preferable ether derivative of compound (Ia) is selected from following compounds:
(xi) an ether derivative of compound (Ia) wherein the ether residue is selected from the group consisting of a C1-C21 alkyl group; a C2-C21 alkenyl or alkynyl group having 1 to 3 double or triple bonds; a C1-C21 alkyl group which has 1 to 3 substituents selected from the group consisting of lower alkoxy, halo and nitro groups; a C1-C21 alkyl group which has 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groups; and a C6-C10 aryl group which is optionally substituted with 1 to 4 is substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groups.
(xii) an ether derivative of compound (Ia) wherein the ether residue is selected from the group consisting of a C1-C21 alkyl group; a C2-C21 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group which has 1 to 4 substituents selected from the group consisting of C1-C4 alkoxy, halo and nitro group; a C1-C6 alkyl group which has 1 to 3 C6-C10 aryl groups which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups; and a C6-C10 aryl group which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups.
(xiii) an ether derivative of compound (Ia) wherein the ether residue is selected from the group consisting of a C1-C21 alkyl group; C6-C20 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy and nitro groups; C1-C6 alkyl group which has 1 to 3 substituents selected from the group consisting of halo group; a C1-C4 alkyl group which has 1 to 3 phenyl or naphthyl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen and nitro groups; and a phenyl or naphthyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups.
(xiv) an ether derivative of compound (Ia) wherein the ether residue is selected from the group consisting of a C6-C20 alkyl group a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy and nitro groups; a C1-C4 alkyl group which has 1 to 3 substituents selected from the group consisting of fluoro and chloro groups; a C1-C4 alkyl group which has 1 to 3 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups; and a phenyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
(xv) an ether derivative of compound (Ia) wherein the ether residue is selected from the group consisting of a C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy, fluoro, chloro, and nitro groups; a C1-C4 alkyl group which has 1 to 3 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups, and a phenyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
(xvi) an ether derivative of compound (Ia) wherein the ether residue is selected from the group consisting of a C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy group; and a C1-C4alkyl group which has 1 or 2 phenyl groups optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C4 alkyl. C1-C4 alkoxy, fluoro and chloro groups.
(xvii) an ether derivative of compound (Ia) wherein the ether residue is selected from the group consisting of a C6-C20 alkyl group and a C10-C20 alkenyl group having 1 to 3 double bonds.
A preferable N-alkylcarbamoyl derivative of compound (Ia) is selected from the following compounds:
(xviii) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue of the N-alkylcarbamoyl derivative is selected from the group consisting of a C1-C21 alkyl group; a C2-C21 alkenyl or alkynyl group having 1 to 3 double or triple bonds; a C1-C21 alkyl group which has 1 to 4 substituents selected from the group consisting of lower alkoxy, halo and nitro groups; and a C1-C21 alkyl group which has 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 4 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groups.
(xix) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue is selected from the group consisting of a C1-C21 alkyl group; a C2-C21 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group which has 1 to 4 substituents selected from the group consisting of C1-C4 alkoxy, halo and nitro groups; and a C1-C6 alkyl group which has 1 to 3 C6-C10 aryl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro group.
(xx) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue is selected from the group consisting of a C1-C21 alkyl group; a C6-C20 alkenyl group having 1 to 3 double bonds; a C2-C6 alkynyl group having one triple bond; a C1-C6 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy and nitro groups; a C1-C6 alkyl group which has 1 to 3 substituents selected from the group consisting of halo groups; and a C1-C4 alkyl group which has 1 to 3 phenyl or naphthyl groups which are optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo and nitro groups.
(xxi) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue is selected from the group consisting of a C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy and nitro groups; a C1-C4 alkyl group which has 1 to 3 substituents selected from the group consisting of fluoro and chloro groups; and a C1-C4 alkyl group which has 1 to 3 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
(xxii) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue is selected from the group consisting of a C6-C20 alkyl group; a C10C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy, fluoro, chloro and nitro groups; and a C1-C4 alkyl group which has 1 to 3 phenyl groups which are optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl, C1-C4 alkoxy, fluoro and chloro groups.
(xxiii) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue is selected from the group consisting of C6-C20 alkyl group; a C10-C20 alkenyl group having 1 to 3 double bonds; a C3-C5 alkynyl group having one triple bond; a C1-C4 alkyl group which has one substituent selected from the group consisting of C1-C4 alkoxy groups; and C1-C4 alkyl group which has 1 or 2 phenyl groups optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C2 alkyl C1-C4 alkoxy, fluoro and chloro groups.
(xxiv) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue is selected from the group consisting of a C6-C20 alkyl group and a C10-C20 alkenyl group having 1 to 3 double bonds.
A more preferable compound (Ia) is selected from group (i) to (iii); group (iv) to (x); group (xi) to (xvii); group (xviii) to (xxiv) in optional combination of these groups, for example:
(xxv) a compound (Ia) wherein the protecting group for a hydroxy group is (i) and the ester residue is (iv).
(xxvi) a compound (Ia) wherein the protecting group for a hydroxy group is (ii) and the ester residue is (v).
(xxvii) a compound (Ia) wherein the protecting group for a hydroxy group is (iii) and the ester residue is (vi).
(xxviii) a compound (Ia) wherein the protecting group for a hydroxy group is (i) and the ether residue is (xi).
(xxix) a compound (Ia) wherein the protecting group for a hydroxy group is (ii) and the ester residue is (xii).
(xxx) a compound (Ia) wherein the protecting group for a hydroxy group is (iii) and the ether residue is (xiii).
(xxxi) a compound (Ia) wherein the protecting group for a hydroxy group is (i) and the alkyl residue is (xviii).
(xxxii) a compound (Ia) wherein the protecting group for a hydroxy group is (ii) and the alkyl residue is (xix).
(xxxiii) a compound (Ia) wherein the protecting group for a hydroxy group is (iii) and the residue is (xx).
The following Tables 1 and 2 are intended to illustrate typical compounds (I) and (Ia) of the present invention and are not intended to limit the scope of this invention.
In Tables 1 and 2
Exemp. comp. No. is exemplification compound number,
CH2 is methylene group,
Me is methyl group,
OH is hydroxy group,
A6 is hexanoyl group,
A7is heptanoyl group,
A8 is octanoyl group,
A9 is nonanoyl group,
A10 is decanoyl group,
A12 is lauroyl group,
A14 is myristoyl group,
A15 is pentadecanoyl group,
A16 is palmitoyl group,
A17 is heptadecanoyl group,
A18 is stearoyl group,
A20 is arachidoyl group,
A22 is behenoyl group,
AO7 is heptanoyloxy group,
AO8 is octanoyloxy group,
AO9 is nonanoyloxy group,
AO10 is decanoyloxy group,
AO12 is lauroyloxy group,
AO14 is myristoyloxy group,
AO15 is pentadecanoyloxy group,
AO16 is palmitoyloxy group,
AO17 is heptadecanoyloxy group,
AO 18 is stearoyloxy group,
AO20 is arachidoyloxy group,
AO22 is behenoyloxy group,
OLE is oleoy group,
LE is linoleoyl group,
LEN is linolenoyl group,
CES is cis-11-eicosenoyl group,
CDS is cis-13-docosenoyl group,
DPP is 3,3-diphenylpropionyl group,
TMPP is 3-(3,4,5-trimethoxyphenyl)propionyl group,
NPP is 2-(4-nitrophenyl)propionyl group,
MPP is 3-(4-methylphenyl)propionyl group,
CP is 3-chloropropionyl group,
ND is 12-nitrodecanoyl group,
TCN is trans-cinnamoyl group,
MP is 3-methoxypropionyl group,
CPA is 4-chlorophenylacetyl group,
BZ is benzoyl group,
NBZ is nitrobenzoyl group,
CB is 3-chlorobenzoyl group,
MB is 2-methoxybenzoyl group,
EB is 4-ethylbenzoyl group,
OLEO is oleoyloxy group,
LEO is linoleoyloxy group,
LENO is linolenoyloxy group,
CESO is cis-11-eicosenoyloxy group,
CDSO is cis-13-docosenoyloxy group,
DPPO is 3,3-diphenylpropionyloxy group,
TMPPO is 3-(3,4,5-trimethoxyphenyl)propionyloxy group,
NPPO is 2-(4-nitrophenyl)propionyloxy group,
MPPO is 3-(4-methylphenyl)propionyloxy group,
CPO is 3-chloropropionyloxy group,
NDO is 12-nitrodecanoyloxy group,
TCNO is trans-cinnamoyloxy group,
MPO is 3-methoxypropionyloxy group,
CPAO is 4-chlorophenylacetyloxy group,
BZO is benzoyloxy group,
NBZO is nitrobenzoyloxy group,
CBO is 3-chlorobenzoyloxy group,
MBO is 2-methoxybenzoyloxy group,
EBO is 4-ethylbenzoyloxy group,
MO is 2-methyloctanoyl group,
MD is 2-methyldecanoyl group,
MDD is 2-methyldodecanoyl group,
MTD is 2-methyltetradecanoyl group,
MHD is 2-methylhexadecanoyl group,
DMO is 2,2-dimethyloctanoyl group,
DMD is 2,2-dimethyldecanoyl group,
DMDD is 2,2-dimethyldodecanoyl group,
DMTD is 2,2-dimethyltetradecanoyl group,
DMHD is 2,2-dimethylhexadecanoyl group,
C2 is ethyl group,
C3 is propyl group,
C4 is butyl group,
C5 is pentyl group,
C6 is hexyl group,
C7 is heptyl group,
C8 is octyl group,
C9 is nonyl group,
C10 is decyl group,
C11 is undecyl group,
C12 is dodecyl group,
C13 is tridecyl group,
C14 is tetradecyl group,
C15 is pentadecyl group,
C16 is hexadecyl group,
C6OC is hexyloxycarbonyl group,
C7OC is heptyloxycarbonyl group,
C8OC is octyloxycarbonyl group,
C9OC is nonyloxycarbonyl group,
C10OC is decyloxycarbonyl group,
C11OC is undecyloxycarbonyl group,
C12OC is dodecyloxycarbonvl group,
MMA10 is 2-methyldecanoyl group,
MMA12 is 2-methyldodecanoyl group,
MMA14 is 2-methyltetradecanoyl group,
DMA10 is 2.2-dimethyldecanoyl group,
DMA12 is 2,2-dimethyldodecanoyl group,
DMA14 is 2,2-dimethyltetradecanoyl group,
In a compound of formula (Ib):
the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group represents A-500359A (exemplification compound No. 1);
the compound wherein R1 is a methyl group, R2 is a hydrogen atom, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group represents A-500359C (exemplification compound No. 2);
the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydrogen atom, R5a is a hydrogen atom and X is a methylene group represents A-500359D (exemplification compound No. 3);
the compound wherein R1 is a hydrogen atom, R2 is a hydrogen atom, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group represents A-500359G (exemplification compound No. 45); and
the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a hydrogen atom and X is a sulfur atom represents A-500359M-2 (exemplification compound No. 396).
In Tables 1 and 2:
preferable compounds include compounds of exemplification compound No. (exemp. comp. No.) 1 to 254, 280 to 283, 309 to 312, 338 to 341, 367 to 370, 396 to 482, 508 to 513, 537 to 588, 592 to 704, 708 to 820, 891 to 910, 914 to 990, 1091 to 1160, 1164 to 1210, 1214 to 1240, 1341 to 1390, 1394 to 1401 and 1405 to 1412;
more preferable compounds include compounds of exemplification compound No. 1 to 3, 7to 11, 45, 49 to 53, 90 to 94, 131 to 135, 172 to 176, 213 to 217, 396, 400 to 404, 537 to 543, 550 to 556, 563 to 569, 576 to 582, 592 to 600, 708 to 716, 891 to 908, 921 to 940, 1091 to 1108, 1121 to 1158,1171 to 1190, 1341 to 1358 and 1371 to 1390;
most preferable compounds include compounds of exemplification compound No. 1 to 3, 7 to 11, 45, 49 to 53, 90 to 94, 131 to 135, 537 to 543, 550 to 556, 563 to 569, 576 to 582, 594, 710, 891, 895, 925, 1091, 1141, 1145, 1175 and 1341;
that is
exemp.comp.No.1 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.2 represents the compound wherein R1 is a methyl group, R2 is a hydrogen atom, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.3 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydrogen atom, R5a is a hydrogen atom and X is a methylene group:
exemp.comp.No.7 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a decanoyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group:
exemp.comp.No.8 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a lauroyl group, R4a is a hydroxy group. R5a is a hydrogen atom and X is a methylene group
exemp.comp.No.9 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a myristoyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.10 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a pentadecanoyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.11 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a palmitoyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.45 represents the compound wherein R1 is a hydrogen atom, R2 is a hydrogen atom, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.49 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a decanoyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.50 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a lauroyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.51 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a myristoyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group,
exemp.comp.No.52 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a pentadecanoyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.53 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a palmitoyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.90 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a decanoyl group and X is a methylene group;
exemp.comp.No.91 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a lauroyl group and X is a methylene group;
exemp.comp.No.92 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a myristoyl group and X is a methylene group: exemp.comp.No.93 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a pentadecanoyl group and X is a methylene group;
exemp.comp.No.94 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a palmitoyl group and X is a methylene group;
exemp.comp.No.131 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a decanoyl group and X is a methylene group;
exemp.comp.No.132 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a lauroyl group and X is a methylene group;
exemp.comp.No.133 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a myristoyl group and X is a methylene group;
exemp.comp.No.134 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a pentadecanoyl group and X is a methylene group;
exemp.comp.No.135 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a palmitoyl group and X is a methylene group;
exemp.comp.No.537 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hexyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.538 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a heptyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.539 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is an octyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.540 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a nonyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.541 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a decyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.542 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is an undecyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.543 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a dodecyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.550 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a hexyloxycarbonyl group and X is a methylene group;
exemp.comp.No.551 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom. R4a is a hydroxy group, R5a is a heptyloxycarbonyl group and X is a methylene group;
exemp.comp.No.552 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is an octyloxycarbonyl group and X is a methylene group;
exemp.comp.No.553 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a nonyloxycarbonyl group and X is a methylene group;
exemp.comp.No.554 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a decyloxycarbonyl group and X is a methylene group;
exemp.comp.No.555 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is an undecyloxycarbonyl group and X is a methylene group;
exemp.comp.No.556 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a dodecyloxycarbonyl group and X is a methylene group;
exemp.comp.No.563 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hexyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.564 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a heptyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.565 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is an octyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.566 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a nonyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.567 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a decyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.568 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is an undecyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.569 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a dodecyloxycarbonyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.576 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a hexyloxycarbonyl group and X is a methylene group;
exemp.comp.No.577 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a heptyloxycarbonyl group and X is a methylene group;
exemp.comp.No.578 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is an octyloxycarbonyl group and X is a methylene group;
exemp.comp.No.579 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a nonyloxycarbonyl group and X is a methylene group;
exemp.comp.No.580 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a decyloxycarbonyl group and X is a methylene group;
exemp.comp.No.581 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is an undecyloxycarbonyl group and X is a methylene group;
exemp.comp.No.582 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a hydrogen atom, R4a is a hydroxy group, R5a is a dodecyloxycarbonyl group and X is a methylene group;
exemp.comp.No.594 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3a is a decyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.710 represents the compound wherein R1 is a hydrogen atom, R2 is a methyl group, R3a is a decyl group, R4a is a hydroxy group, R5a is a hydrogen atom and X is a methylene group;
exemp.comp.No.891 represents the compound wherein R1 is a methyl group, R11 is a methyl group, R3 is a hydrogen atom, and R5 is a hydrogen atom;
exemp.comp.No.895 represents the compound wherein R1 is a methyl group, R11 is a methyl group, R3 is a decanoyl group, and R5 is a hydrogen atom;
exemp.comp.No.925 represents the compound wherein R1 is a methyl group, R11 is a methyl group, R3 is a hydrogen atom, and R5 is a decanoyl group;
exemp.comp.No.1091 represents the compound wherein R1 is a methyl group, R11 is a dodecyl group, R3 is a hydrogen atom, and R5 is a hydrogen atom;
exemp.comp.No.1141 represents the compound wherein R1 is a hydrogen atom, R11 is a methyl group, R3 is a hydrogen atom, and R5 is a hydrogen atom;
exemp.comp.No.1145 represents the compound wherein R1 is a hydrogen atom, R11 is a methyl group, R3 is a decanoyl group, and R5 is a hydrogen atom;
exemp.comp.No.1175 represents the compound wherein R1 is a hydrogen atom, R11 is a methyl group, R3 is a hydrogen atom, and R5 is a decanoyl group; and
exemp.comp.No.1341 represents the compound wherein R1 is a hydrogen atom, R11 is a dodecyl group, R3 is a hydrogen atom, and R5 is a hydrogen atom.
Compounds of the present invention represented by the formula (I) or (Ia) can be prepared by the process as described below.
Compounds A-500359A (Exemp. compound No. 1), A-500359C (Exemp. compound No. 2), A-500359D (Exemp. compound No. 3), A-500359G (Exemp. compound No. 45) and A-500359M-2 (Exemp. compound No. 396) of the present invention each represented by the formula (I) are available by culturing a microorganism capable of producing the above described compounds, belonging to the Streptomyces spp. on a suitable medium and then recovering the compound from the cultured broth, Streptomyces griseus Strain SANK60196 (which will hereinafter be called xe2x80x9cStrain SANK60196xe2x80x9d), a preferable microorganism capable of producing Compounds A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 has been collected and separated from the soil of Mt. Tsukuba/Ibaraki-ken in a manner known to those skilled in the art.
Mycological properties of Strain SANK60196 are as follows:
1) Morphological Appearance
Strain SANK60196 showed morphological appearance as described below after cultivation at 28xc2x0 C. for 14 days on a medium specified by International Streptomyces Project (which will hereinafter be abbreviated as xe2x80x9cISPxe2x80x9d) [refer to Shirling, E. B. and Gottlieb, D., xe2x80x9cInt. J. Syst. Bacteriol. 16.313-340 (1996)xe2x80x9d.] Observation through an optical microscope indicates that substrate mycelia of SANK60196 are favourably grown and branched and show yellowish grey, yellowish brown or pale olive colour, but unlike the strain belonging to Nocardia spp., does not show cleavage or zigzag extension. Aerial mycelia exhibit simple branching. The form of the spore chain is straight or cursed and its chain is formed of 10 to 50 or greater spores. Observation through a scanning electron microscope shows that the spore has an oval shape and it has a smooth surface structure. The spore is 0.6-0.8xc3x970.7-1.2 mm in dimension. The spore is formed only on the aerial mycelia. Formation of sporangia, axial division of aerial cleavage of aerial mycelia and sclerotia are not recognized.
2) Growth Characteristics on Various Culture Media
Growth characteristics of Strain SANK60196 on an agar medium after cultivation at 28xc2x0 C. for 14 days is as described below in Table 3. In the Table, the composition of the medium attached with ISP No. is the same as specified by ISP. In the item, abbreviations G. AM. R and SP stand for growth, aerial mycelia, reverse colour and soluble pigment, respectively. The colour tone is described in accordance with xe2x80x9cColour Standards. ed. by Japan Colour Laboratoryxe2x80x9d. The indication of the colour tone in parentheses is a colour number in accordance with Munsell colour system. The pale yellow soluble pigment produced in a water-agar medium changes into colourless by 0.05N hydrochloric acid, but shows no change by 0.05N sodium hydroxide.
[Table 3]
Nature of Medium;
Item: characteristics
Yeast extractxe2x80x94malt extract agar (ISP 2);
G: Excellent, flat, yellowish brown (10YR 5/6)
AM: Abundantly formed, velvety, pale brown (2.5Y 8/2)
R: Yellowish brown (10YR 5/8)
SP: Yellowish brown (10YR 6/8)
Oat mealxe2x80x94agar (ISP 3);
G: Excellent, flat, yellowish brown (2.5Y 6/6)
AM: Abundantly formed, velvety, pale yellowish orange (5Y 9/2)
R: Dark yellow (2.5Y 818)
SP: Not produced
Starchxe2x80x94inorganic salt agar (ISP 4);
G: Good, flat, yellowish brown (2.5Y 6/4)
AM: Abundantly formed, velvety, yellowish grey (7.5Y 9/2)
R: Yellowish brown (2.5Y 6/4)
Glycerinxe2x80x94asparagine agar (ISP 5);
G: Excellent, flat, pale yellowish brown (2.5Y 7/6)
AM: Abundantly formed, velvety, yellowish grey (5Y 8/2)
R: Pale yellowish brown (2.5Y 8/6)
SP: Not produced
Peptonexe2x80x94yeast extractxe2x80x94iron agar (ISP 6);
G: Excellent, flat, pale olive color (5Y 8/3)
AM: Slightly produced, velvet), yellowish grey (5Y 9/1)
R: Pale yellow (5Y 8/6)
SP: Not produced
Tyrosine agar (ISP 7);
G: Good, flat, grayish yellow brown (2.5Y 5/4)
AM: Abundantly formed, velvety, light olive grey (7.5Y 8/2)
R: Yellowish brown (10YR 5/4)
SP: Grayish yellow brown (2.5Y 4/3)
Sucrosexe2x80x94nitrate agar;
G: Not so good, flat, pale yellow (5Y 8/6)
AM: Abundantly formed, velvety, light olive grey (7.5Y 8/2)
R: Dark yellow (5Y 8/8)
SP: Pale yellow (5Y 9/6)
Glucosexe2x80x94asparagine agar;
G: Good, flat, pale yellow (5Y 9/3)
AM: Not so good, velvety, yellowish grey (5Y 9/1)
R: Yellowish grey (7.5Y 9/3)
SP: Not produced
Nutrient agar (product of Difco Laboratories);
G: Good, flat, pale yellowish brown (2.5Y 8/3)
AM: Good, velvety, yellowish grey (5Y 9/1)
R: Yellowish grey (5Y 9/4)
SP: Not produced
Potato extractxe2x80x94carrot extract agar;
G: Not so good, flat, yellowish grey (7.5Y 9/2)
AM: Not so good, velvet, yellowish grey (5Y 9/2)
R: Yellowish grey (7.5Y 9/3)
SP: Yellowish grey (7.5Y 9/3)
Water agar;
G: Not good, flat, yellowish grey (5Y 9/1)
AM: Not good, velvety, yellowish grey (5ZY 9/1)
R: Yellowish grey (7.5Y 9/4)
SP: Pale yellow (5Y 9/6)
3) Physiological Characteristics
The physiological characteristics of the present strain observed for 2 to 21 days after cultivation at 28xc2x0 C. are as shown in Table 4. In the table Medium 1 is a yeast extractxe2x80x94malt extract agar medium (ISP 2).
Utilisation of a carbon source by Strain SANK60196 observed after cultivation at 28xc2x0 C, for 14 days on a Pridham-Gottlieb agar medium (ISP 9) is as described in Table 5. In the table, xe2x80x9c+xe2x80x9d means utilisable, while xe2x80x9cxe2x88x92xe2x80x9d means non-utilisable.
4) Chemotaxonomic Properties
The cell wall of the present strain was investigated in accordance with the method of Hasegawa, et al. [refer to Hasegawa. T., et al., xe2x80x9cThe Journal of General and Applied Microbiology, 29, 319-322(1983)], resulting in the detection of LL-diaminopimelic acid. The main sugar component in the whole cells of the present strain was investigated in accordance with the method of M. P. Lechevalier [refer to Lechevalier, M. P., xe2x80x9cJournal of Laboratory and Clinical Medicine. 71, 934-944(1968)]. As a result, no characteristic component was detected.
The above-described mycological properties have revealed that the present strain belongs to Streptomyces spp. among the actinomycetes. It has been made clear that the present strain is markedly related to Streptomyces griseus, as a result of comparison with the microorganism described in the ISP strains by Shirling and Gottlieb [refer to Shirling, E. B. and Gottlieb, D., xe2x80x9cInternational Journal of Systematic Bacteriology, 18, 68-189 and 279-392 (1968); 19, 391-512 (1969); 22, 265-394 (972)xe2x80x9d], the microorganism described in xe2x80x9cThe actinomycetes Vol. 2xe2x80x9d written by Waksman [refer to Waksman, S. A., xe2x80x9cThe actinomycetes 2 (1961)xe2x80x9d], with the microorganism described in Bergey""s Manual edited by Buchanan and Gibbons [refer to R. E. Buchanan and N. E. Gibbons. xe2x80x9cBergey""s Manual of Determinative Bacteriologyxe2x80x9d, 8th edition (1974)], with the microorganism described in xe2x80x9cBergey""s Manual of Systematic Bacteriologyxe2x80x9d, edited by Williams [refer to Williams, S. T., et al., xe2x80x9cBergey""s Manual of Systematic Bacteriology 4 (1989)xe2x80x9d] and with the microorganism described in the recent literature about actinomycetes belonging to Streptomyces spp. It has however been recognized to be different from Streptomyces griseus, because it produces a yellowish grey soluble pigment on a glycerin-asparagine agar medium and a pale yellowish brown soluble pigment on a peptone-yeast extractxe2x80x94iron agar medium but produces a soluble pigment neither on a potato extractxe2x80x94carrot extract agar medium nor on a water agar medium; the maximum growth temperature is 40xc2x0 C.; and it is grown in the presence of 7% of salt.
The present strain having such mycological characteristics is considered to be a novel strain different from Streptomyces griseus, but it is impossible to distinguish them based on only the above-described differences. The present inventors therefore identified the present strain as Streptomyces griseus SANK60 196.
This strain was internationally deposited with Agency of Industrial Science and Technology, Ministry of International Trade and Industry (1-3, Higashi 1-chome Tsukuba-shi, Ibaraki-ken, 305, JAPAN) as of Feb. 22, 1996, with the accession number of FERM BP-5420.
A description was heretofore made on Strain SANK60196. It is known that various properties of actinomycetes are not fixed but easily change naturally or synthetically. The strain usable in the present invention embraces all of such variants. In other words. the present invention embraces all the strains belonging, to the Streptomyces spp. and capable of producing Compounds A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2.
Any synthetic or natural medium can be used for cultivation for microorganisms capable of producing Compounds A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 of the present invention, insofar as it contains, as needed, a substance selected from carbon sources, nitrogen sources, inorganic ions and organic nutrition sources.
Known carbon sources, nitrogen sources and inorganic salts conventionally employed for cultivation of the strain of the eumycetes or actinomycetes and are utilisable by a microorganism can be used as such nutrition sources.
Specific examples of the carbon source include glucose, fructose, maltose, sucrose, mannitol, glycerol, dextrin, oats, rye, corn starch, potato, corn meal, soybean meal, cotton seed oil, thick malt syrup, theriac, soybean oil, citric acid and tartaric acid. They may be used either singly or in combination. The amount of the carbon source to be added usually varies, but not limited to, within a range of from 1 to 10 wt. %.
As the nitrogen source. a substance containing protein or hydrolyzate thereof can usually be employed. Preferred examples of the nitrogen source include soybean meal, wheat bran, peanut meal, cotton seed meal, casein hydrolyzate, Farmamine, fish meal, corn steep liquor, peptone, meat extract, pressed yeast, dry yeast, yeast extract, malt extract, potato, ammonium sulfate, ammonium nitrate and sodium nitrate. It is preferred to use the nitrogen source either singly or in combination in an amount ranging from 0.2 to 6 wt. % of the amount of the medium.
As the nutrition inorganic salt, ordinarily employed salts from which an ion is available, such as sodium salts, ammonium salts, calcium salts, phosphates, sulfates, chlorides and carbonates can be used. In addition, trace metals such as potassium, calcium, cobalt manganese, iron and magnesium are usable.
For the production of Compound A-500359A, the addition of cobalt or yeast extract is particularly effective.
Upon culturing the microorganism capable of producing Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2, an inhibitor of antibiotic biosynthesis can be added to produce useful related compounds. Compound A500359M-2 can be produced, for example, by using, as a medium additive, S-(2-aminoethyl)-L-cysteine or salt thereof which is an aspartate kinase inhibitor. The additive can be added to give its final concentration ranging from 1 to 100 mM. Preferably, use of it to give a final concentration of 10 mM permits favorable production of Compound A-500359M-2.
Upon liquid culture, a silicone oil, vegetable oil or surfactant can be added as an antifoamer.
The medium used for the cultivation of Strain SANK 60196 to produce Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 preferably has a pH ranging from 5.0 to 8.0.
The temperature which allows Strain SANK60196 to grow ranges from 12 to 36xc2x0 C. It is preferred to cultivate the strain at 18 to 28xc2x0 C. in order to produce Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2, of which 19 to 23xc2x0 C. is more preferred.
Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 is available by aerobic culture of Strain SANK 60196. Ordinarily-employed solid culture, shake culture, and aeration agitation culture can be used as such culturing method.
For small-scale culturing, agitation of the culture for several days at 19 to 23xc2x0 C. is preferred. Culturing is started by growing a seed culture in a single or two stage process in an Erlenmeyer flask equipped with a baffle (water flow adjusting wall) or an ordinarily-employed Erlenmeyer flask. A carbon source and a nitrogen source can be used in combination as a medium in the seed culture. The flask or seed culture may be shaken at 19 to 23xc2x0 C. for 5 days or until the seed cultures grow sufficiently in a thermostat incubator. The seed cultures thus grown can be used for inoculation of the second seed culture medium or a production medium. When the seed cultures are used under an intermediate growing step, they are allowed to grow essentially in a similar manner, followed by inoculation of a part of them into a production medium. The flask into which the seed cultures has been inoculated is subjected to culturing with shaking at a constant temperature for several days and after completion of the culturing, the cultured medium in the flask is centrifuged or filtered.
For large-scale cultivation. on the other hand, culturing in a jar fermenter or tank equipped with an agitator and an aeration apparatus is preferred. Prior to culturing in such a container, the culture medium is heated to 125xc2x0 C. for sterilization. After cooling, the seed cultures which have been allowed to grow in advance by the above-described method are inoculated on the sterilized medium. Then, culturing is carried out with aeration and agitation at 19 to 23xc2x0 C. This method is suitable for obtaining a large amount of compounds.
Compound A-500359M-2 can be produced by adding, as an aspartate kinase inhibitor, an aqueous solution of S-(2-aminoethyl)-L-cysteine or salt thereof which has been filter sterilized in advance to a sterilized medium at the beginning time of the cultivation or during cultivation.
The production of Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 produced can be measured by sampling a portion of the cultured broth and subjecting it to high performance liquid chromatography. The titre of Compound A-500359A, A-500359C, A-500359D, A-500359G or A-5003 59M-2 usually reaches a peak in 3 to 9 days.
After completion of the cultivation, the cell component is separated from the cultured broth by separation with the aid of diatomaceous earth or centrifugation. Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 present in the filtrate or supernatant is purified by utilizing its physico-chemical properties with HPLC analytical data as an index. Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 present in the filtrate can be purified by using adsorbents singly or in combination, such as activated charcoal (product of Wako Pure Chemicals) and an adsorbing resin such as xe2x80x9cAmberlite XAD-2 or XAD-4xe2x80x9d (trade name; product of Rohm and Haas), and xe2x80x9cDiaion HP-10, HP-20, CHP-20P or HP-50, Sepabeads SP205, SP206 or SP207xe2x80x9d (trade name; product of Mitsubishi Chemical). Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 in the solution can be separated from impurities by passing a solution containing them through the layer of such adsorbents, or by eluting the adsorbed compounds from the layer with aqueous methanol. aqueous acetone or aqueous normal butanol.
Compounds A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 thus obtained can be purified by adsorption column chromatography using an adsorbent such as silica gel, xe2x80x9cFlorisilxe2x80x9d (trade name), or xe2x80x9cCosmosilxe2x80x9d (trade name; product of Nacalai Tesque); partition column chromatography using xe2x80x9cSephadex LH-20xe2x80x9d (trade name; product of Pharmacia Biotech): gel filtration chromatography using xe2x80x9cToyopearl HW40Fxe2x80x9d (trade name; product of TOSOH Corp); or high performance liquid chromatography using a normal phase or reversed phase column; or the like.
Compounds A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 according to the present invention can be separated and purified by using the above-exemplified separation and purification means singly or in combination as needed, or in some cases, by using one of them in repetition.
Compounds A-500359A, A-500359C, A-500359D, A-500359G and A-500359M-2 of the present invention thus obtained are novel compounds not published in the literature but their antibacterial activity can be determined by a method known to those skilled in the art.
Ester derivatives, ether derivatives and N-alkylcarbamoyl derivatives can each be prepared easily by using any one of the below-described Processes A to F or using them in combination as necessary.
(Process A)
Process A is for the preparation of an ester derivative of Compound (Ia) and by this process, Compound (Ic) wherein R2 is a methyl group can be prepared.
Process A 
wherein: R1 and X have the same meanings as described above, R3b represents a hydrogen atom or a hydroxy-protecting group, R3c represents a hydrogen atom, a hydroxy-protecting group or an ester residue, R4b represents a hydrogen atom, a hydroxy-protecting group or an ester residue, R5b represents a hydrogen atom or a hydroxy-protecting group, and R5c represents a hydrogen atom, a hydroxy-protecting group or an ester residue, with the proviso that R3b and R5b do not represent a hydrogen atom at the same time and R3c, R4b and R5c do not all represent a hydrogen atom or a hydroxy-protecting group at the same time.
Step A1 is for the preparation of a compound having the formula (III) and it is accomplished by protecting the hydroxy group of the compound of formula (II).
Although the hydroxy-protecting step differs depending on the kind of the protecting group, it is conducted by a process well known in synthetic organic chemistry.
When the hydroxy-protecting group is a xe2x80x9csilyl groupxe2x80x9d, xe2x80x9calkoxymethyl groupxe2x80x9d, xe2x80x9csubstituted ethyl groupxe2x80x9d, xe2x80x9caralkyl groupxe2x80x9d, xe2x80x9calkoxycarbonyl groupxe2x80x9d, xe2x80x9calkenyloxycarbonyl groupxe2x80x9d, xe2x80x9caralkyloxcarbonyl groupxe2x80x9d, xe2x80x9c1-(aliphatic acyloxy)-lower alkyl groupxe2x80x9d, xe2x80x9c1-(aliphatic acylthio)-lower alkyl groupxe2x80x9d, xe2x80x9c1-(cycloalkylcarbonyloxy)-lower alkyl groupxe2x80x9d, xe2x80x9c1-(aromatic acyloxy)-lower alkyl groupxe2x80x9d, xe2x80x9c1-(lower alkoxycarbonyloxy)-lower alkyl group, xe2x80x9c1-(cycloalkyloxycarbonyloxy )-lower alkyl groupxe2x80x9d, xe2x80x9cphthalidyl groupxe2x80x9d, xe2x80x9coxodioxolenylmethyl groupxe2x80x9d, xe2x80x9ccarbamoyl group substituted with 2 lower alkyl groupsxe2x80x9d, xe2x80x9c1-(lower alkoxycarbonloxy )-lower alkyl aroupxe2x80x9d, xe2x80x9clower alkyl-dithioethyl groupxe2x80x9d or xe2x80x9c1-(acyloxy)-alklyloxycarbonyl groupxe2x80x9d, this step is conducted by reacting Compound (II) with a desired hydroxy-protecting group halide in an inert solvent in the presence of a base.
Examples of the hydroxy-protecting, group halide usable in the above reaction include trimethylsilyl chloride triethylsilyl chloride, t-butyldimethylsilyl chloride. t-butyldimethylsilyl bromide, methyldi-t-butylsilyl chloride, methyldi-t-butlsilyl bromide, diphenylmethylsilyl chloride, diphenylmethylsilyl bromide, methoxymethyl chloride, 2-methoxyethoxymethyl chloride, 2.2.2-trichloroethoxymethyl chloride, 1-ethoxyethyl chloride, benzyl chloride, benzyl bromide, xcex1-naphthylmethyl chloride, diphenylmethyl chloride, diphenylmethyl bromide, triphenylmethyl chloride, 4-methylbenzyl chloride, 4-methoxybenzyl chloride, 4-nitrobenzyl chloride, 4-chlorobenzyl chloride, methoxycarbonyl chloride, ethoxycarbonyl chloride, 2,2,2-trichloroethoxycarbonyl chloride, vinyloxycarbonyl chloride, allyloxycarbonyl chloride, benzyloxycarbonyl chloride, benzyloxycarbonyl bromide, 4-methoxybenzyloxycarbonyl chloride, 4-nitrobenzyloxycarbonyl chloride, acetoxymethyl chloride, propionyloxymethyl chloride, butyryloxymethyl chloride, pivaloyloxymethyl chloride, pivaloyloxymethyl bromide, valeryloxymethyl chloride, 1-acetoxyethyl chloride, butyrloxyethyl chloride, 1-pivaloyloxyethyl chloride, cyclopentylcarbonyloxymethyl chloride, cyclohexylcarbonyloxymethyl chloride, 1-cyclopentylcarbonyloxyethyl chloride, 1-cyclohexylcarbonyloxyethyl chloride, methoxycarbonyloxymethyl chloride, methoxycarbonyloxymethyl bromide, ethoxycarbonyloxymethyl chloride, propoxycarbonyloxymethyl chloride, isopropoxycarbonyloxymethyl chloride, butoxycarbonyloxymethyl chloride, isobutoxycarbonyloxymethyl chloride, 1-(methoxycarbonyloxy)ethyl chloride, 1-(methoxycarbonyloxy)ethyl bromide, 1-(ethoxycarbonyloxy)ethyl chloride, 1-(isopropoxycarbonyloxy)ethyl chloride, cyclopentyloxycarbonyloxymethyl chloride, cyclohexyloxycarbonyloxymethyl chloride, 1-(cyclopentyloxycarbonyloxy)ethyl chloride, 1-(cyclohexyloxycarbonyloxy)ethyl chloride, phthalidyl chloride, phthalidyl bromide, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl chloride, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl chloride, (5-methyl-2-oxo-1,3-dioxolen-4-yl )methyl chloride, (5-methyl-2-oxo-1.3-dioxolen-4-yl)methyl bromide, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl chloride, dimethylcarbamoyl chloride, diethylcarbamoyl chloride, methyldithioethyl chloride, ethyldithioethyl chloride and pivaloyloxymethyloxycarbonyl chloride, of which triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldimethylsilyl bromide, benzyl chloride, benzyl bromide, triphenylmethyl chloride, 4-methoxybenzyl chloride, 2,2,2-trichloroethoxycarbonyl chloride, allyloxycarbonyl chloride, benzyloxycarbonyl chloride, benzyloxycarbonyl bromide, acetoxymethyl chloride and pivaloyloxymethyl chloride are preferred.
Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide, and organic amines such as triethylamine, tributylamine N-methylmorpholine, pyridine, 4-dimethylaminopyridine, picoline, lutidine, collidine, 1,5-diazabicyclo[4.3.0]-5-nonene and 1,8-diazabicyclo[5.4.0]-7-undecene. Out of these, organic amines are preferred, of which triethylamine, tributylamine, pyridine and lutidine are particularly preferred. Upon use of an organic amine in the liquid form, it also serves as a solvent when used in large excess.
There is no particular limitation on the inert solvent used in the above reaction, provided it is inert to the reaction. Examples include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers such as ether, tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide; and mixtures thereof. Of these, hydrocarbons and amides are preferred.
Although the reaction temperature differs with the nature of the starting compound (II), the halide and the solvent, it usually ranges from xe2x88x9210xc2x0 C. to 100xc2x0 C. (preferably 0 to 50xc2x0 C.). Although the reaction time differs with the reaction temperature or the like, it ranges from 30 minutes to 5 days (preferably 1 to 3 days).
When the hydroxy-protecting group is a xe2x80x9ctetrahydropyranyl or tetrahydrothiopyranyl groupxe2x80x9d or a xe2x80x9ctetrahydrofuranyl or tetrahydrothiofuranyl groupxe2x80x9d, Compound (II) is reacted with a cyclic ether compound such as dihydropyran, 3-bromodihydropyran, 4-methoxydihydropyran, dihydrothiopyran, 4-methoxydihydrothiopyran, dihydrofuran or dihydrothiofuran in an inert solvent in the presence of an acid.
Examples of the acid usable in the above reaction include inorganic acids such as hydrogen chloride, nitric acid, hydrochloric acid and sulfuric acid and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid, of which hydrogen chloride, hydrochloric acid, sulfuric acid and trifluoroacetic acid are preferred, with hydrogen chloride and hydrochloric acid being particularly preferred.
Examples of the inert solvent usable in the above reaction (which is inert to the reaction) include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers such as ether, tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, arnides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide; and mixtures thereof. Of these, hydrocarbons and ethers are preferred.
Although the reaction temperature differs with the nature of the starting compound (II), the cyclic ether compound and the solvent, it usually ranges from xe2x88x9210xc2x0 C. to 100xc2x0 C. (preferably 0 to 50xc2x0 C.). Although the reaction time differs with the reaction temperature or the like, it usually ranges from 30 minutes to 5 days (preferably 1 to 3 days).
When the hydroxy-protecting group is a xe2x80x9ccarbamoyl groupxe2x80x9d or xe2x80x9ccarbamoyl group substituted with one lower alkyl groupxe2x80x9d. Compound (II) is reacted with an isocyanate or lower alkyl isocyanate such as methyl isocyanate or ethyl isocyanate in an inert solvent in the presence or absence of a base.
Preferred examples of the base usable in the above reaction include the above-exemplified organic amines, with triethylamine, tributylamine, pyridine and lutidine being particularly preferred.
There is no particular limitation on the inert solvent used in the above reaction provided that it is inert to the reaction. Examples include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers such as ether, tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, nitrites such as acetonitrile. amides such as N,N-dimethylfornamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide: and mixtures thereof. Of these, hydrocarbons and ethers are preferred.
Although the reaction temperature differs with the nature of the starting compound (II), the cyclic ether compound and the solvent, it usually ranges from xe2x88x9210xc2x0 C. to 100xc2x0 C. (preferably 0 to 50xc2x0 C.). Although the reaction time differs with the reaction temperature or the like. it ranges from 30 minutes to 5 days (preferably 1 to 3 days).
After completion of the reaction, the desired compound in each reaction is collected from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by filtering off any insoluble matter, as required, and then distilling off the solvent under reduced pressure: or by distilling off the solvent under reduced pressure, adding water to the residue, extracting the mixture with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate or the like and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example. by recrystallization, column chromatography or the like.
Step A2 is for the preparation of a compound having the formula (Ic). This step can be accomplished by esterifying Compound (III) and if desired, removing the hydroxy-protecting group from the esterified compound.
Esterification is conducted by reacting Compound (III) with an acid halide or acid anhydride having a desired ester residue in an inert solvent in the presence of a base.
Examples of the acid halide or acid anhydride used in the above reaction include compounds represented by any one of the formulae R6COxe2x80x94Y, R6CO2CO2R9, R6COxe2x80x94Oxe2x80x94COR6 and R6OCOxe2x80x94Y [wherein R6 has the same meaning as described above. Y represents a halogen atom, preferably chlorine or bromine, R9 represents a C1-4 alkyl group (preferably ethyl or isopropyl)]; a mixed acid anhydride of formic acid and acetic acid, cyclic acid anhydrides such as succinic acid anhydride, glutaric acid anhydride and adipic acid anhydride: and phosphate ester introducing agents such as compounds represented by the formula (R7O)2POxe2x80x94Y (wherein Y has the same meaning as described above and R7 represents a lower alkyl group), of which the compounds represented by any one of the formulas R6COxe2x80x94Y, R6CO2CO2R9, R6COxe2x80x94Oxe2x80x94COR6 and R6OCOxe2x80x94Y (wherein R6, Y and R9 have the same meanings as described above) are preferred.
Examples of the base usable in the above reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide, and organic amines such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, picoline, lutidine, collidine, 1,5-diazabicyclo[4.3.0]-5-nonene and 1,8-diazabicyclo[5.4.0]-7-undecene. Of these, organic amines are preferred, of which triethylamine, tributylamine, pyridine and lutidine are particularly preferred. Upon use of an organic amine in the liquid form, it also serves as a solvent when used in large excess.
When the esterifying reaction is a phosphate ester introducing reaction, it can also be conducted by reacting Compound (III) with a phosphite having a desired ester residue in an inert solvent in the presence of an acid or base, and oxidizing the reaction mixture into the corresponding phosphate ester by an oxidizing agent.
As the phosphite, a compound represented by the formula (R7O)2xe2x80x94Pxe2x80x94Z, wherein R7 represents a C6-20 alkyl group and Z represents a halogen atom or a compound represented by the formula xe2x80x94N(R8)2 (wherein R8 represents a lower C6-20 alkyl group)] can be used.
When, in the above formula, Z represents a halogen atom, a base is employed as a catalyst and examples of the base usable are similar to those exemplified above. When Z is not a halogen atom, on the other hand, an acid is used as a catalyst. Any acid can be used, provided that it exhibits acidity as strong as acetic acid. Tetrazole is preferred.
Examples of the oxidizing agent usable in the above reaction include meta-chloroperbenzoic acid, t-butylhydroperoxide and peracetic acid, of which meta-chloroperbenzoic acid is preferred.
There is no particular limitation on the inert solvent usable in the above reaction, provided that it is inert to the reaction. Examples include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers such as ether, tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, nitrites such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide; and mixtures thereof. Of these. hydrocarbons and amides are preferred.
Although the reaction temperature differs with the nature of the starting compound (III), the phosphite and the solvent, it usually ranges from xe2x88x9210xc2x0 C. to 100xc2x0 C. (preferably 0 to 50xc2x0 C.). The reaction time differs with the reaction temperature and the like, but it ranges from 10 minutes to 2 days (preferably 30 minutes to 10 hours).
Esterification can also be conducted by reacting Compound (III) with a carboxylic acid having a desired ester residue in an inert solvent in the presence of a condensing agent.
Examples of the condensing agent usable in the above reaction include carbodiimides such as dicyclohexylcarbodiimide, carbonyl diimidazole and 1-(N,N-dimethylaminopropyl)-3-methylcarbodiimide hydrochloride, of which dicyclohexylcarbodiimide is preferred.
There is no particular limitation on the inert solvent used in the above reaction. provided that it is inert to the reaction. Examples include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. ethers such as ether, tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide; and mixtures thereof. Of these, hydrocarbons, halogenated hydrocarbons and amides are preferred.
Although the reaction temperature differs with the nature of the starting compound (III), carboxylic acid and solvent. it usually ranges from xe2x88x9210xc2x0 C. to 100xc2x0 C. (preferably 0 to 50xc2x0 C.). The reaction time differs with the reaction temperature or the like, but it usually ranges from 10 minutes to 2 days (preferably 30 minutes to 10 hours).
After completion of the reaction. the desired compound in each reaction is recovered from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by filtering off any insoluble matter, as necessary, and then distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue, extracting the mixture with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate or the like and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, by recrystallization, column chromatography or the like.
Although the desired deprotection of hydroxy-protecting group differs with the kind of protecting group, it is conducted by the process well known in synthetic organic chemistry.
When the hydroxy-protecting group is an xe2x80x9caralkyl groupxe2x80x9d or xe2x80x9caralkyloxycarbonyl groupxe2x80x9d, deprotection is conducted by contacting the corresponding compound with a reducing agent (including catalytic reduction) or oxidizing agent in an inert solvent.
There is no particular limitation on the inert solvent usable in the removal by catalytic reduction, provided that it is inert to the reaction. Examples include alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as toluene, benzene and xylene and aliphatic hydrocarbons such as hexane and cyclohexane and esters such as ethyl acetate and propyl acetate and aliphatic acids such as acetic acid, and mixtures of the above-exemplified organic solvent and water, of which alcohols are preferred.
Although there is no particular limitation on the catalyst usable in the above reaction (provided that it is ordinarily employed for catalytic reduction), examples include palladium on carbon. Raney nickel, platinum oxide, platinum black, rhodium-aluminium oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate, of which palladium on carbon is preferred.
Although there is no particular limitation on the pressure of hydrogen, it usually ranges from 1 to 10 times atmospheric pressure (preferably 1 to 3 times atmospheric pressure).
Although the reaction temperature or reaction time differs with the nature of the starting substance, the solvent and the catalyst, the reaction temperature usually ranges from xe2x88x9220xc2x0 C. to 100xc2x0 C. (preferably 0 to 50xc2x0 C.) and the reaction time usually ranges from 30 minutes to 10 hours (preferably 1 to 5 hours).
There is no particular limitation on the inert solvent usable upon deprotection by an oxidizing agent, provided that it is inert to the reaction. Examples include ketones such as acetone, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, nitriles such as acetonitrile, ethers such as diethyl ether, tetrahydrofuran and dioxane, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoramide and sulfoxides such as dimethylsulfoxide, and mixed solvents thereof. Preferred are the amides and sulfoxides.
There is no particular limitation imposed on the oxidizing agent usable in the above reaction, provided that it may be employed for oxidization. Examples include alkali metal persulfates such as potassium persulfate and sodium persulfate, ceric ammonium nitrate (CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), of which ceric ammonium nitrate (CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) are preferred.
Although the reaction temperature and reaction time differs with the nature of the starting substance, the solvent and the catalyst, the reaction temperature usually ranges from xe2x88x9210xc2x0 C. to 150xc2x0 C. (preferably 0 to 50xc2x0 C.) and the reaction time usually ranges from 10 minutes to 24 hours (preferably 30 minutes to 10 hours).
When the hydroxy-protecting group is a t-butyl group, t-butoxycarbonyl group, xe2x80x9calkoxymethyl groupxe2x80x9d, xe2x80x9ctetrahydropyranyl or tetahydrothiopyranyl groupxe2x80x9d or xe2x80x9ctetrahydrofuranyl or tetrahydrothiofuranyl groupxe2x80x9d, deprotection is conducted by reacting the corresponding compound with an acid in an inert solvent.
There is no particular limitation on the inert solvent used in the above reaction, provided that it is inert to the reaction. Examples include hydrocarbons such as hexane and benzene, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, esters such as ethyl acetate, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, ethers such as ether, tetrahydrofuran and dioxane; and mixtures thereof with water. Of these, esters, ethers and halogenated hydrocarbons are preferred.
Examples of the acid usable here include inorganic acids such as hydrogen chloride, nitric acid, hydrochloric acid and sulfuric acid, organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid and Lewis acids such as boron trifluoride, of which the inorganic acids and organic acids are preferred and hydrochloric acid, sulfuric acid and trifluoroacetic acid are particularly preferred.
The reaction temperature usually ranges from xe2x88x9210xc2x0 C. to 100xc2x0 C. (preferably xe2x88x925 to 50xc2x0 C.). Although the reaction time differs with the reaction temperature or the like, it ranges from 5 minutes to 48 hours (preferably 30 minutes to 10 hours).
When the hydroxy-protecting group is a xe2x80x9csilyl groupxe2x80x9d, deprotection may be conducted by reacting the corresponding compound with a compound containing a fluoride anion, such as tetrabutylammonium fluoride, in an inert solvent.
There is no particular limitation on the inert solvent used in the above reaction insofar as it is inert to the reaction. Examples include hydrocarbons such as hexane and benzene, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, esters such as ethyl acetate, ketones such as acetone and methyl ethyl ketone, and ethers such as ether, tetrahydrofuran and dioxane; and mixtures thereof with water. Of these, ethers are preferred.
Although there is no particular limitation imposed on the reaction temperature or reaction time, the reaction temperature usually ranges from xe2x88x9210 to 50xc2x0 C. (preferably 0 to 30xc2x0 C.) and the reaction time usually ranges from 2 to 24 hours (preferably 10 to 18 hours).
After completion of the reaction, the desired compound in this reaction is separated from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by neutralizing the reaction mixture as needed, filtering off any insoluble matter, adding a water-immiscible organic solvent such as ethyl acetate to the filtrate, washing the resulting mixture with water and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, by recrystallization, reprecipitation, column chromatography or the like.
If desired, the hydroxy group of the resulting compound can be esterified or protected.
Esterification of Compound (II) by using 1 to 3 molar equivalents of an esterifying agent can produce a mixture of a compound having 1 to 3 esterified hydroxy groups. By separating the compound from the mixture by column chromatography or the like and then protecting its hydroxy group if desired. Compound (Ic) is also available.
(Process B)
Process B is for the preparation of an ester derivative of Compound (Ia). By this process, Compound (Id), wherein R2 is a methyl group, an xe2x80x94Oxe2x80x94 ester residue is present at the 2xe2x80x2-position, a hydroxy group or xe2x80x94Oxe2x80x94 ester residue is present at the 2xe2x80x3-position and a hydroxy group or xe2x80x94Oxe2x80x94 ester residue is present at the 3xe2x80x3-position can be prepared.
Process B 
wherein: R1 and X have the same meanings as described above, R3d represents an ester residue, R4b represents a hydrogen atom or an ester residue and R5d represents a hydrogen atom or an ester residue.
Step B1 is a step for preparing a compound of formula (IIIa). This step is conducted by reacting a compound of formula (IIa) with an acetonide agent in an inert solvent in the presence of an acid catalyst.
Examples of the acetonide agent usable in the above reaction include acetone, methoxyisopropene and 2,2-dimethoxypropane, of which acetone and 2,2-dimethoxypropane are preferred.
Examples of the acid catalyst usable in the above reaction include inorganic acids such as hydrogen chloride, nitric acid, hydrochloric acid and sulfuric acid, organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid. Lewis acids such as boron trifluoride and acidic resins such as xe2x80x9cAmberlyst 15xe2x80x9d, of which organic acids and acidic resins are preferred, with p-toluenesulfonic acid and xe2x80x9cAmberlyst 15xe2x80x9d, being more preferred.
The reaction temperature usually ranges from xe2x88x9210 to 100xc2x0 C. (preferably 0 to 50xc2x0 C.). Although the reaction time differs with the reaction temperature and the like, it usually ranges from 1 hour to 7 days (preferably 10 hours to 3 days).
After completion of the reaction, the desired compound in this reaction is recovered from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by neutralizing the reaction mixture as needed, filtering off any insoluble matter, adding a water-immiscible organic solvent such as ethyl acetate to the filtrate, washing the resulting mixture with water and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, by recrystallization, reprecipitation, column chromatography or the like.
Step B2 is for the preparation of a compound represented by the formula (Id). This step is accomplished by esterifying Compound (IIIa), removing an isopropylidene group from the esterified compound and then esterifying the hydroxy group if desired.
Esterification is conducted as in the corresponding reaction described in Step A2, while the reaction to remove the isopropylidene group is conducted by reacting the corresponding compound with an acid as in Step B1 while using, as an inert solvent, water, an alcohol such as methanol or ethanol or aqueous alcohol.
(Process C)
Process C is for the preparation of an ester derivative of Compound (Ia). By this process, it is possible to prepare Compound (Ie) wherein R2 represents a methyl group, a protected or unprotected hydroxy group or an xe2x80x94Oxe2x80x94 ester residue is present at the 2xe2x80x3-poisition, and a protected or unprotected hydroxy group or an xe2x80x94Oxe2x80x94 ester residue is present at the 3xe2x80x3-position.
Process C 
wherein: R1 and X have the same meanings as described above, R3e represents a hydrogen atom, a hydroxy-protecting group or an ester residue, and R5e represents a hydrogen atom, a hydroxy-protecting group or an ester residue, with the proviso that R3e and R5e represent neither a hydrogen atom nor a hydroxy-protecting group simultaneously.
Step C1 is a step for preparing Compound (Ie) and this step is accomplished by esterifying the compound of the formula (IIb) and, if desired, protecting the hydroxy group.
Esterification is conducted as in the corresponding reaction described in Step A2. A mixture of monoesters may be obtained by the use of an esterifying agent in an amount of about 1 molar equivalent. This mixture can be easily separated by column chromatography or the like. Use of the esterifying agent in an amount of about 2 molar equivalents yields a diester.
The hydroxy-protecting reaction is conducted in a similar manner to that described in Step A1.
(Process D)
Process D is for the preparation of an ester derivative of Compound (Ia). By this process. Compound (If) having a protected or unprotected hydroxy group or an ester residue at the 2xe2x80x2-position, a protected or unprotected hydroxy group or an ester residue at the 3xe2x80x2-position, a protected or unprotected hydroxy group or an xe2x80x94Oxe2x80x94 ester residue at the 2xe2x80x3-position and a protected or unprotected hydroxy group or an xe2x80x94Oxe2x80x94 ester residue at the 3xe2x80x3-position can be prepared.
Process D 
wherein: R1 and X have the same meanings as described above, R2a represents a hydrogen atom, a hydroxy-protecting group or an ester residue, R3f represents a hydrogen atom, a hydroxy-protecting group or an ester residue, R4c represents a hydrogen atom, a hydroxy-protecting group or an ester residue, and R5f represents a hydrogen atom, a hydroxy-protecting group or an ester residue, with the proviso that all of R2a, R3f, R4c and R5f represent neither a hydrogen atom nor a hydroxy-protecting group simultaneously.
Step D1 is a step for the preparation of Compound (If). It can be accomplished by protecting the diol portion of a compound having the formula (IIc) with an isopropylidene group, esterifying the resulting compound, removing the isopropylidene group from the esterified compound and then, esterifying or protecting the hydroxy group if desired.
The protection of the diol portion with an isopropylidene group is conducted in a similar manner to that in Step B1. Use of about 1 molar equivalent yields a mixture of a compound protected at the 2xe2x80x2- and 3xe2x80x2-positions and a compound protected at the 2xe2x80x3- and 3xe2x80x3-positions. The mixture can easily be separated, for example, by column chromatography.
Esterification is conducted in a similar manner to the corresponding reaction in Step A2. Use of an esterifying agent in an amount of about 1 molar equivalent yields a mixture of monoesters. This mixture can easily be separated, for example, by column chromatography. Use of the esterifying agent in an amount of about 2 molar equivalents yields a diester.
The reaction to remove the isopropylidene group is conducted in a similar manner to the corresponding reaction in Step B2.
The esterification of the resulting compound, which is conducted as desired, is conducted in a similar manner to the corresponding reaction in Step A2. Use of an esterifying agent in an amount of about 1 molar equivalent yields a mixture of monoesters. This mixture can easily be separated, for example, by column chromatography. Use of the esterifying agent in an amount of about 2 molar equivalents yields a diester. The hydroxy-protecting reaction of the compound thus obtained is conducted in a similar manner to Step A1. Use of a protecting agent in an amount of about 1 molar equivalent yields a mixture of compounds each having one protected hydroxy group. This mixture can easily be separated, for example, by column chromatography. Use of the protecting agent in an amount of about 2 molar equivalents yields a compound having two protected hydroxy groups.
Compound (If) is also available by esterifying the compound of the formula (IIc) with 1 to 4 molar equivalents of an esterifying agent, separating the resulting mixture, for example, by column chromatography and if desired, protecting the hydroxy group.
(Process E)
Process E is for the preparation of an ether derivative of formula (Ig) and (Ih) of Compound (Ia).
Process E 
wherein: R1 and X have the same meanings as described above, R10 represents the above-described ether residue and L represents a protecting group for the nitrogen atom of the uracil residue.
Step E1 is a step for preparing a compound represented by formula (IV) by reacting a compound of formula (IIIa) with an alkylation protecting reagent represented by the formula LY (wherein L and Y have the same meanings as described above) in an inert solvent in the presence of a base.
Examples of the alkylation protecting reagent (LY) usable in the above reaction include 4-methoxybenzyloxymethyl chloride, pivaloyloxymethyl chloride and acetoxymethyl chloride, of which 4-methoxybenzyloxymethyl chloride is preferred.
Examples of the base usable in the above reaction include tertiary amines such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and alkali metal hydrides such as sodium hydride and potassium hydride, of which 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is preferred.
Examples of the solvent usable in the above reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane and amides such as N,N-dimethylformamide and N,N-dimethylacetamide, of which N,N-dimethylformamide is preferred.
The reaction temperature usually ranges from xe2x88x9230 to 100xc2x0 C. (preferably xe2x80x9410 to 30xc2x0 C.). Although the reaction time differs with the reaction temperature and the like, it usually ranges from 30 minutes to 1 day (preferably 1 hour to 5 hours).
After completion of the reaction. the desired compound in this reaction is recovered from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by neutralizing the reaction mixture as needed, filtering off any insoluble matter, adding a water-immiscible organic solvent such as ethyl acetate or methylene chloride to the filtrate, washing the resulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueous solution of sodium bicarbonate or saturated saline, drying over anhydrous magnesium sulfate or anhydrous sodium sulfate and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, recrystallization, reprecipitation, column chromatography or the like.
Step E2 is a step for preparing a compound of the formula (V) by reacting a compound of the formula (IV) with an alkylating agent having a desired ether residue in an inert solvent in the presence of a base.
Examples of the alkylating agent usable in the above reaction include alkyl halides and alkyl triflates, of which an alkyl iodide is preferred.
Examples of the base usable in the above reaction include tertiary amines such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and alkali metal hydrides such as sodium hydride and potassium hydride, of which sodium hydride is preferred.
Examples of the solvent usable in the above reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane and amides such as N,N-dimethylformamide and N,N-dimethylacetamide, of which N,N-dimethylformamide is preferred.
The reaction temperature usually ranges from xe2x88x9230 to 100xc2x0 C. (preferably xe2x80x9410 to 30xc2x0 C.). Although the reaction time differs with the reaction temperature and the like, it usually ranges from 1 hour to 2 days (preferably 1 hour to 10 hours).
After completion of the reaction, the desired compound in this reaction is recovered from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by neutralizing the reaction mixture as needed, filtering off any insoluble matter, adding a water-immiscible organic solvent such as ethyl acetate or methylene chloride to the filtrate, washing the resulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueous solution of sodium bicarbonate or saturated saline, drying over anhydrous magnesium sulfate or anhydrous sodium sulfate and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, recrystallization, reprecipitation, column chromatography or the like.
Step E3 is a step for preparing a compound of the formula (Ig) by reacting a compound of the formula (V) with an agent capable of deprotecting the protected uracil residue in an inert solvent.
When the protecting group contained in the uracil residue in the formula (V) is a 4-methoxybenzyloxymethyl group, examples of the deprotecting agent usable here include 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or cerium (IV) ammonium nitrate (CAN) [preferably 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)], while examples of the solvent usable include water, alcohols such as methanol and ethanol, and halogenated hydrocarbons such as methylene chloride and chloroform, and mixtures thereof (preferably a mixed solvent of methylene chloride and water). The reaction temperature usually ranges from 0 to 150xc2x0 C. (preferably 10 to 100xc2x0 C.). Although the reaction time differs with the reaction temperature and the like, it usually ranges from 1 hour to 2 days (preferably 1 hour to 10 hours).
When the protecting group contained in the uracil group in the formula (V) is a pivaloyloxymethyl or acetoxymethyl group, examples of the deprotecting agent usable here include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, aqueous ammonia, and amines such as methylamine and ethylamine (preferably sodium hydroxide or potassium carbonate). Examples of the solvent include water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and mixtures thereof (preferably a mixed solvent of the alcohols and ethers with water). The reaction temperature usually ranges from 0 to 100xc2x0 C. (preferably 10 to 50xc2x0 C.). Although the reaction time differs with the reaction temperature and the like. it usually ranges from 10 minutes to 1 day (preferably 1 hour to 10 hours).
After completion of the reaction, the desired compound in the above reaction is recovered from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by neutralizing the reaction mixture as needed, filtering off any insoluble matter, adding a water-immiscible organic solvent such as ethyl acetate or methylene chloride to the filtrate, washing the resulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueous solution of sodium bicarbonate or saturated saline as needed, drying over anhydrous magnesium sulfate or anhydrous sodium sulfate and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, by recrystallization, reprecipitation, column chromatography or the like.
Step E4 is a step for preparing a compound of the formula (Ih) by reacting a compound of the formula (Ig) with an acid catalyst in an inert solvent.
Examples of the acid catalyst include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, organic acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid and p-toluenesulfonic acid. Lewis acids such as boron trifluoride and acidic resins such as xe2x80x9cAmberlyst 15xe2x80x9d, of which acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and xe2x80x9cAmberlyst 15xe2x80x9d are preferred.
Examples of the solvent include water, alcohols such as methanol and ethanol and ethers such as dioxane and tetrahydrofuran, and mixed solvents of the alcohol or ether with water, of which methanol is preferred.
The reaction temperature usually ranges from 0 to 150xc2x0 C. (preferably 10 to 80xc2x0 C.). Although the reaction time differs with the reaction temperature and the like, it usually ranges from 1 hour to 2 days (preferable 3 hours to 1 day).
After completion of the reaction, the desired compound in this reaction is recovered from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by neutralizing the reaction mixture as needed, filtering off any insoluble matter, adding a water-immiscible organic solvent such as ethyl acetate or methylene chloride to the filtrate, washing the resulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueous solution of sodium bicarbonate and saturated saline as needed, and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, by recrystallization, reprecipitation, or column chromatography.
Compound (Ih) thus obtained can be converted to the corresponding hydroxy-protected compound. ester derivative or N-alkylcarbamoyl derivative by any one of Processes A to D and below-described Process F.
(Process F)
Process F is for the preparation of an N-alkylcarbamoyl derivative of the invention compound (Ia).
Process F 
wherein: R1 and X have the same meanings as described above, R11 and R12 each independently represent the N-alkyl residue of the above-described N-alkyl-carbamoyl group and Bz represents a benzoyl group.
Step F1 is a step for preparing a compound of formula (VI) by reacting a compound of formula (II) with a benzoylating agent in an inert solvent in the presence of a base.
Examples of the benzoylating agent include benzoyl chloride, benzoyl bromide and benzoic anhydride, of which benzoic anhydride is preferred.
Examples of the base usable in the above reaction include organic amines such as triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine and 4-dimethylaminopyridine and alkali metal hydrides such as sodium hydride and potassium hydride, of which pyridine and 4-dimethylaminopyridine are preferred.
Examples of the solvent usable in the above reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, halogenated hydrocarbons such as methylene chloride and chloroform, and pyridine, of which pyridine is preferred.
The reaction temperature usually ranges from xe2x88x9230 to 100xc2x0 C. (preferably xe2x88x9210 to 30xc2x0 C.). Although the reaction time differs with the reaction temperature and the like, it usually ranges from 30 minutes to 1 day (preferably 1 hour to 10 hours).
After completion of the reaction, the desired compound in this reaction is recovered from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by neutralizing the reaction mixture if necessary, filtering off any insoluble matter, adding a water-immiscible organic solvent such as ethyl acetate or methylene chloride to the filtrate, washing the resulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueous solution of sodium bicarbonate and saturated saline as needed, drying over anhydrous magnesium sulfate or anhydrous sodium sulfate, and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, by recrystallization, reprecipitation or column chromatography.
Step F2 is a step for preparing a compound of formula (VII) by reacting a compound of formula (VI) with nitrosylsulfuric acid at 0 to 30xc2x0 C. in an inert mixed solvent of methylene chloride and water and then reacting diazomethane with the reaction mixture at 0 to 30xc2x0 C. in methylene chloride.
After completion of the reaction, the desired compound in this reaction is recovered from the reaction mixture in manner known to those skilled in the art. The desired compound can be obtained, for example, by neutralizing the reaction mixture as needed filtering off any insoluble matter, adding a water-immiscible organic solvent such as ethyl acetate or methylene chloride to the filtrate, washing the resulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueous solution of sodium bicarbonate and saturated saline as needed, drying over anhydrous magnesium sulfate or anhydrous sodium sulfate and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, by recrystallization, reprecipitation or column chromatography.
Step F3 is a step for preparing a compound of the formula (Ii) by reacting a compound of the formula (VII) with an amine in an inert solvent.
Examples of the solvent usable in the above reaction include water, alcohols such as methanol and ethanol and amides such as N,N-dimethylformamide and N,N-dimethylacetamide, of which alcohols are preferred.
The reaction temperature usually ranges from 0 to 100xc2x0 C. (preferably 10 to 60xc2x0 C.). Although the reaction time differs with the reaction temperature and the like, it usually ranges from 30 minutes to 1 day (preferably 1 hour to 10 hours).
After completion of the reaction, the desired compound in this reaction is recovered from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by neutralizing the reaction mixture as needed, filtering off any insoluble matter, adding a water-immiscible organic solvent such as ethyl acetate or methylene chloride to the filtrate, washing the resulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueous solution of sodium bicarbonate and saturated saline as needed, drying over anhydrous magnesium sulfate or anhydrous sodium sulfate and then distilling off the solvent. If necessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, by recrystallization, reprecipitation or column chromatography.
Compound (Ii) thus obtained can be converted to the corresponding hydroxy-protected compound, ester derivative or ether derivative by using any one of the above-described Processes A to E.
The present invention also provides;
(1) Compound A-500359E represented by the following formula (XI): 
or a salt thereof;
(2) Compound A-500359F represented by the following formula (XII): 
or a salt thereof;
(3) Amide derivative of Compound A-500359F represented by the following formula (XIII): 
or a salt thereof;
(4) Compound A-500359H represented by the following formula (XIV): 
or a salt thereof;
(5) Compound A-500359J represented by the following formula (XV): 
or a salt thereof;
(6) Compound A-500359M-3 represented by the following formula (XVI): 
or a salt thereof;
(7) a process for preparing the compound as described in (1), (2), (4) or (5) by cultivating a microorganism capable of producing said compound and belonging to the Streptomyces spp. and recovering the compound from the cultured broth;
(8) a process as described in (7), wherein the microorganism belonging to the Streptomyces spp. and capable of producing the compound is Streptomyces griseus SANK60196 (FERM BP-5420) and is capable of producing the compounds as described in (1), (2), (4), or (5);
(9) a microorganism which belongs to the Streptomyces spp. and is capable of producing the compound as described in (1), (2), (4) or (5);
(10) a microorganism as described in (9) which is Streptomyces griseus SANK60196 (FERM BP-5420);
(11) a process for preparing the compound as described in (1), (4) or (5) by cultivating a microorganism (which belongs to the Streptomyces spp. and is capable of producing the compound) by using, singly or in combination, S-(2-aminoethyl)-L-cysteine, salts thereof and L-allylglycine as an additive to a medium and collecting the compound as described in (1), (2), (4) or (6) from the cultured broth;
(12) a composition for the treatment or prevention of infectious diseases which contains the compound as described in (1), (2), (3), (4), (5) or (6) or a pharmacologically acceptable salt thereof as an effective ingredient;
(13) use of the compound as described in (1), (2), (3), (4), (5) or (6) or a pharmacologically acceptable salt thereof for the preparation of a medicament for treating or preventing infectious diseases; and
(14) a method of treating or preventing infectious diseases, which comprises administering, to a warm-blooded animal, a pharmacologically effective amount of the compound as described in (1), (2), (3), (4), (5) or (6) or a pharmacologically acceptable salt thereof.
Compounds of the present invention represented by any one of the formulae (XI), (XII), (XIII), (XIV), (XV) and (XVI) are produced in the culture broth of Streptomyces griseus Strain SANK60196 which belongs to the Streptomyces spp. and has been separated from the soil collected from Mt. Tsukuba/Igaraki-ken; or produced by microbial conversion in the cultivation process or chemical conversion in the isolation and purification process.
Compound A-500359E of the formula (XI), Compound A-500359F of the formula (XII), Amide derivative of Compound A-500359F of the formula (XIII).
Compound A-500359H of the formula (XIV), Compound A-500359J of the formula (XV) and Compound A-500359M-3 of the formula (XVI) of the present invention each contain asymmetric carbons, and each may therefore exist as various optical isomers. In the present invention, isomers of each of Compound A-500359E, Compound A-500359F, Amide derivative of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3 are represented by the same formula, but the present invention embraces all the isomers including racemic compounds and also mixtures thereof. When a stereospecific synthesis process is adopted or an optically active compound is employed as a starting compound, the isomer of each of Compound A-500359E, Compound A-5000359F, Amide derivative of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3 may be prepared directly or, if it is prepared in the form of a mixture, each isomer may be obtained in a manner known to those skilled in the art.
Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3 of the present invention can each be converted into the corresponding salt by a method known to those skilled in the art. The present invention embraces such salts of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3. There is no particular restriction on the nature of the salt of any of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3, provided that it is medically employed and is pharmacologically acceptable. When the salt of Compound A-500359F, Compound A-500359H, Compound A-500359J or Compound A-500359M-3 is employed for the purpose other than a medicament, for example, employed as an intermediate, no limitation is imposed. Preferred examples of such a salt include alkali metal salts such as a sodium salt, a potassium salt, or a lithium salt, alkaline earth metal salts such as a calcium salt or a magnesium salt, metal salts such as an aluminium salt, an iron salt, a zinc salt, a copper salt, a nickel salt or a cobalt salt, inorganic salts such as an ammonium salt, organic amine salts such as a t-octylamine salt, a dibenzylamine salt, a morpholine salt, a glucosamine salt, a phenylglycine alkyl ester salt, an ethylenediamine salt, an N-methylglucamine salt, a guanidine salt, a diethylamine salt, a triethylamine salt, a dicyclohexylamine salt, an N,Nxe2x80x2-dibenzylethylenediamine salt, a chloroprocaine salt, a procaine salt, a diethanolamine salt, a N-benzylphenethylamine salt, a piperazine salt and a tetraamethylammonium salt, or a tris(hydroxymethyl)aminomethane salt, and amino acid salts such as a glycine salt, a lysine salt, an arginine salt, an ornithine salt, or an asparagine salt. More preferred are salts preferably usable as a pharmacologically acceptable salt such as a sodium salt, a potassium salt and an ammonium salt.
Compound A-500359E, Compound A-500359F, Amide derivative of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3 of the present invention and salts thereof may each exist as a solvate. For example, when they are allowed to stand in the air or recrystallized, water is adsorbed thereto by absorption or a hydrate may be formed. Such a solvate is also embraced in the present invention.
The present invention also embraces all the compounds, so-called prodrugs, which will be converted into Compound A-500359E, Compound A-500359F, Amide derivative of compound A-500359F, Compound A-500359H, Compound A-500359J or Compound A-500359M-3 by metabolism in vivo.
Compound A-500359E, Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3 of the present invention which are represented by the formulae (XI), (XII), (XIV), (XV) and (XVI) respectively are available by culturing, in a suitable medium, a microorganism belonging to the Streptomyces spp. and recover from the cultured broth. Streptomyces griseus Strain SANK 60196 (which will hereinafter be called xe2x80x9cStrain SANK60196xe2x80x9d), preferred as the microorganism capable of producing Compound A-500359E, Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3 are, as described above, collected and isolated from the soil of Ttsukubasan/Ibaraki Prefecture in a conventional manner. Strain SANK60196 has the biological characteristics as described above.
The various characteristics of the actinomycetes belonging to Streptomyces spp. such as Strain SANK60196 are not stable, but as is well known, they easily change naturally or artificially. The strains usable in the present invention include all such variants. The present invention embraces all the strains belonging to the Streptomyces spp. and capable of producing Compound A-500359E, Compound A-500359F, Compound A-500359H, Compound A-500359J or Compound A-500359M-3.
Any synthetic or natural medium is usable as a medium for culturing the microorganism capable of producing Compound A-500359E, Compound A-500359F, Compound A-500359H, Compound A-500359J or Compound A-500359M-3, insofar as it contains a source selected from carbon sources, nitrogen sources, inorganic ions and organic nutrition sources as necessary.
Examples of the nutrition source usable here include knows carbon sources, nitrogen sources and inorganic salts which are conventionally used for the cultivation of a mycotic or actinomycete strain and are utilisable by microorganisms.
Specific examples of the carbon source include glucose, fructose, maltose, sucrose, mannitol, glycerol, dextrin, oats, rye, corn starch, potato, corn meal, soybean meal, cotton seed oil, glutinous malt syrup, syrup, soybean oil, citric acid and tartaric acid. They may be used either singly or in combination. The amount of the carbon source to be added usually varies, but is not limited to, within a range of from 1 to 10 wt. % of the amount of the medium.
A substance containing a protein or a hydrolysate thereof is generally employed as the nitrogen source. Preferred examples of the nitrogen source include soybean meal, wheat bran, peanut meal, cotton seed meal, skimmed milk, casein hydrolysate, Pharmamine (product of Sheffield Chemical), fish meal, corn steep liquor, peptone, meat extract, pressed yeast, dry veast, yeast extract, malt extract, potato, ammonium sulfate, ammonium nitrate and sodium nitrate. It is preferred to use the above-exemplified nitrogen sources either singly or in combination in an amount ranging from 0.2 to 6 wt. % of the amount of the medium.
Any ordinarily employed salt containing an ion such as sodium, ammonium, calcium, phosphate, sulfate, chloride or carbonate can be used as the nutrient inorganic salt. In addition, trace of metals such as potassium, calcium, cobalt, manganese, iron and magnesium are usable.
The addition of cobalt, skimmed milk or yeast extract is particularly effective in the production of Compound A-500359E, Compound A-500359F, Compound A-500359H or Compound A-500359J.
Upon culturing the microorganism, an inhibitor of antibiotic biosynthesis can be added to produce Compound A-500359E, Compound A-500359F and Compound A-500359H, Compound A-500359E, Compound A-500359F and Compound A-500359H can each be produced, for example, by using S-(2-aminoethyl)-L-cysteine or salt thereof which is an aspartate kinase inhibitor singly or in combination with cobalt, skimmed milk and yeast extract, as a medium additive. For example, use of the above-described additive in combination with skimmed milk improves productivity of Compound A-500359E, Compound A-500359F and Compound A-500359H. The additive can be added to give its final concentration ranging from 1 to 100 mM. For the production of Compound A-500359E, Compound A-500359F and Compound A-500359H, the final concentration of 10 mM is preferred.
Use of the above-described additive in combination with an amino acid or salt thereof makes it possible to produce useful compounds related to Compound A-500359F and Compound A-500359H. In particular, by the use in combination with L-allylglycine or a salt thereof. Compound A-500359M-3 (XVI) is available. The L-allylglycine can be added at a final concentration ranging from 1 to 100 mM. At the final concentration of 10 mM. Substance A-500359M-3 can be produced preferably.
Upon liquid culture, an antifoamer such as silicone oil, vegetable oil, surfactant or the like can be used.
The medium for cultivation of Strain SANK60196 to produce Compound A-500359E, Compound A-500359F, Compound A-500359H, or Compound A-500359J preferably has a pH ranging from 5.0 to 8.0.
Although the temperature which allows growth of Strain SANK60196 ranges from 12 to 36xc2x0 C. the strain is preferably cultured at 18 to 28xc2x0 C. more preferably 19 to 23xc2x0 C., in order to produce Compound A-500359E, Compound A-500359F, Compound A-500359H and Compound A-500359J.
By in order to obtain Compound A-500359E, Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3, an aerobic culture of Strain SANK60196 can be used. Examples of such a cultivation method include ordinarily employed aerobic culture such as solid culture, shaking culture, and aeration agitation culture.
For small-scale cultivation, shake culture for several days at 19 to 23xc2x0 C. is preferred. Cultivation is started by growing a step of seed culture in a first or second stage process in a baffled Erlenmeyer flask (equipped with a water flow adjusting wall) or an ordinarily-employed Erlenmeyer flask. A carbon source and a nitrogen source can be used in combination as a medium in the seed culture. The seed culture flask may be shaken at 19 to 23xc2x0 C. for 5 days in a thermostat incubator or shaken until the seed culture grows sufficiently. The seed culture thus grown is used for inoculation on the second seed culture medium or a production medium. When the seed cultures are used under an intermediate growing step, they are allowed to grow in a similar manner, followed by partial inoculation into a production medium. The flask into which the seeds have been inoculated is subjected to culturing with shaking at a constant temperature for several days, and after completion of the cultivation, the cultured medium in the flask is centrifuged or filtered.
For large-scale cultivation, on the other hand, use of a jar fermenter or tank equipped with an agitator and an aeration apparatus is preferred. Prior to cultivation in such a container, a nutrient medium is heated to 121 to 130xc2x0 C. for sterilization. After cooling, the seed cultures which have been allowed to grow in advance by the above-described method are inoculated on the sterilized medium. Then, cultivation is carried out with aeration and agitation at 19 to 23xc2x0 C. This method is suitable for preparing a large amount of compounds.
Compound A-500359E, A-500359F or A-500359H can also be produced by adding, as an aspartate kinase inhibitor, an aqueous solution of S-(2-aminoethyl)-L-cysteine or salt thereof which has been previously filter-sterilized in advance to a sterilized medium at the start of, or during, cultivation.
Compound A-500359M-3 can be produced by separately or simultaneously adding aqueous solutions of S-(2-aminoethyl)-L-cysteine or salt thereof, and L-allyl glycine or salt thereof which have been filter sterilized in advance to the sterilized medium at the start of, or during, cultivation.
The product of Compound A-500359E, A-500359F, A-500359H, A-500359J and A-500359M-3 by cultivation can be measured by subjecting a portion of the cultured broth to HPLC analysis. The titre of Compound A-500359E, A-500359F, A-500359H, A-500359J and A-500359M-3 usually reaches a peak in 3 to 15 days.
After completion of the cultivation, the cell component is separated from the cultured broth by filtration with the aid of diatomaceous earth or centrifugation and Compound A-500359E, A-500359F, A-500359H, A-500359J and A-500359M-3 present in the filtrate or supernatant is purified by utilizing their physico-chemical properties with HPLC analytical data as an index. As diatomaceous earth, xe2x80x9cCelite 545xe2x80x9d (product of Celite Corporation) is preferred. Compound A-500359E, A-500359F, A-500359H, A-500359J and A-50359M-3 present in the filtrate can be purified by using adsorbents singly or in combination, for example, activated charcoal or an adsorbing resin such as xe2x80x9cAmberlite XAD-2 or XAD4xe2x80x9d (product of Rohm and Haas), and xe2x80x9cDiaion HP-10, HP-20, CHP-20P, HP-50 or SP207 (each. product of Mitsubishi Chemical). Compound A-500359E, A-500359F, A-500359H. A-500359J and A-500359M-3 can be separated from impurities by passing a solution containing Compound A-500359E, A-500359F, A-500359H, A-500359J and A-5003 59M-3 through the layer of such an adsorbent as described above, and removing the impurities adsorbed thereto from the solution; or by eluting the adsorbed Compound A-500359E, A-500359F, A-500359H, A-500359J and A-500359M-3 with aqueous methanol, aqueous acetone, aqueous n-butanol, aqueous ammonia, ammonia-containing aqueous methanol or ammonia-containing aqueous acetone. When an ammonia-containing solution is employed as an eluent, the amide derivative of compound A-500359F happens to be produced upon elution from the column or concentration.
Compound A-500359E, Compound A-500359F, the amide derivative of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3 thus obtained can be purified by adsorption column chromatography using silica gel, xe2x80x9cFlorisilxe2x80x9d, xe2x80x9cCosmosilxe2x80x9d (product of Nacalai Tesque), or xe2x80x9cDiaion CHP-20P or SP207xe2x80x9d (product of Mitsubishi Chemical); gel filtration chromatography with xe2x80x9cSephadex G-10 (product of Pharmacia Biotech) or xe2x80x9cToyopearl HW40Fxe2x80x9d (product of TOSOH Corporation); anion exchange chromatography with xe2x80x9cDowex 1 or SBR-Pxe2x80x9d (product of Dow Chemical) or xe2x80x9cDiaion PA316xe2x80x9d (product of Mitsubishi Chemical); normal phase and reversed phase HPLC; or the like.
Compound A-500359E, Compound A-500359F, the amide derivative of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3 of the present invention can be separated and purified by using the above-exemplified separation and purification means singly or in combination as needed, or in some cases, by using one of them in repetition.
Compound A-500359F can be obtained by hydrolysis of Compound A-500359E. For example, hydrolysis is preferably conducted under basic conditions, preferably in aqueous basic solution.
Examples of the basic compound usable for hydrolysis include alkali metal hydroxides and weak acid salts thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, sodium carbonate, potassium carbonate and sodium bicarbonate; alkaline earth metal hydroxides and weak acid salts thereof such as calcium hydroxide, magnesium hydroxide and magnesium acetate; inorganic basic compounds and basic salts thereof such as ammonia; organic amines and basic salts thereof such as t-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycine alkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine. chloroprocaine, procaine, diethanolamine, N-benzylphenethylamine, piperazine, tetramethylammonia and tris(hydroxymethyl)aminomethane. A basic buffer containing an alkali metal ion, an alkaline earth metal ion, an inorganic ion such as ammonia, or an organic amine ion of the above-exemplified basic compounds may also be employed. Among them, alkali metal hydroxides are preferred, of which sodium hydroxide is particularly preferred. In particular, hydrolysis of Compound A-500359E by using sodium hydroxide can easily produce Compound A-500359F.
The concentration of the basic compound used in the above-described reaction preferably ranges from 0.001 to 1N, more preferably 0.3 to 0.1N. The reaction temperature is preferably xe2x88x9220 to 40xc2x0 C. more preferably 0 to 30xc2x0 C. The reaction time is preferably 30 seconds to 15 hours, more preferably 30 minutes to 2 hours.
Use of aqueous ammonia as a base produces the amide derivative of Compound A-500359F together with Compound A-500359F, but these compounds can be separated and purified by the above-described method.
The amide derivative of Compound A-500359F may be produced by reacton of Compound A-500359E with ammonia in a solvent.
Examples of the solvent include water and alcohols such as ethanol and methanol, of which water and methanol are preferred.
Gaseous ammonia may be introduced into the solution of the compound, but a solution of ammonia in water or in an alcohol such as methanol or ethanol is usually used. Preferably, an aqueous or methanolic solution is employed.
When aqueous ammonia is employed, its concentration preferably ranges from 0.1 to 1N. more preferably 0.3 to 0.7N. The reaction temperature is preferably xe2x80x9420 to 40xc2x0 C., more preferably 0 to 30xc2x0 C. The reaction time is preferably 30 minutes to 15 hours, more preferably 1 to 4 hours.
When aqueous ammonia is used, in addition to the desired amide derivative of Compound A-500359F, Compound A-500359F is produced by the hydrolysis of the ester. These compounds however can be separated and purified by the above-described methods.
The amide derivative of Compound A-500359F can also be produced by reacting Compound A-500359F with a methylating reagent in a solvent, thereby converting it to the methyl ester derivative, that is, Compound A-500359E, and then reacting the resulting compound with ammonia as described above.
Examples of the methylating reagent include diazomethane and dimethylsulfuric acid, of which diazomethane is preferred. The methylating reagent for the conversion of Compound A-500359F to Compound A-500359E is preferably added in an amount of 1 to 5 equivalents, preferably 1.5 to 2 equivalents.
Examples of the solvent usable for the above reaction include water and alcohols such as methanol and ethanol, of which water and methanol are preferred.
The reaction temperature is preferably xe2x88x9220 to 40xc2x0 C. more preferably 0 to 30xc2x0 C. The reaction time is preferably 30 minutes to 15 hours. more preferably 1 to 2 hours.
After completion of the reaction. Compound A-500359F, Compound A-500359E, and the amide derivative of Compound A-500359F can be isolated from the reaction mixture by the means selected as needed from those described above in the separation and purification means for Compound A-500359E, Compound A-500359F, the amide derivative of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-50359M-3.
Typical preparation processes for Compound A-500359E, Compound A-500359F, the amide derivative of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-50359M-3 are described hereinabove, but preparation processes are not limited thereto and other processes already known to those skilled in the art may also be employed.
Compound A-500359E, Compound A-500359F, the amide derivative of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3 of the present invention thus available are novel compounds which have not been described in the literature. Their growth inhibitory activity against general gram positive bacteria or gram negative bacteria can be determined by the disk assay method using normal agar medium (product of Eiken Chemical) or heart infusion agar medium (product of Difco Laboratories). Growth inhibitory activity against Mycobacteria, gram positive bacteria belonging to the Actinonycetales, can be determined similarly on the above-described medium added further with glycerin.
Typical evaluation methods of biological activity of Compound A-500359E, Compound A-500359F, the amide derivative of Compound A-500359F, Compound A-500359H, Compound A-500359J and Compound A-500359M-3 were described so far, but the evaluation method is not limited thereto, but other evaluation methods already known to those skilled in the art can also be employed.
The compounds of the present invention or pharmacologically acceptable salts thereof may be administered through various routes. Examples include oral administration using tablets, capsules, granules, powders, syrups or the like; and parenteral administration using injections (intravenous, intramuscular or subcutaneous), drops, suppositories or the like. These formulations can be prepared in a conventional manner by adding to a medicament ordinarily employed carriers known in the field of pharmaceutical formulation technique such as an excipient, binder, disintegrator, lubricant, corrigent, adjuvant for solubilization, suspending agent, coating agent, diluent and/or the like.
For the formation of tablets, various carriers known conventionally in this field can be employed. Examples include excipients such as lactose, sucrose, sodium chloride, glucose, urea starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinyl pyrrolidone, disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic monoglyceride, starch and lactose; disintegration suppressants such as sucrose, stearin, cacao butter and hydrogenated oil; absorption facilitators such as quaternary ammonium salts and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch lactose, kaolin, bentonite and colloidal silicic acid; and lubricants such as purified talc, stearates, boric acid powder and polyethylene glycol. Tablets can be formed as those having ordinary coating as needed such as sugar coated tablets, gelatin encapsulated tablets, enteric coated tablets, film coated tablets, or double or multiple layer tablets.
For the formation of pills, various carriers conventionally known in this field can be used. Examples include excipients such as glucose, lactose, cacao butter, starch, hardened vegetable oil, kaolin and talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; and disintegrators such as laminaran ajar.
For the formation of suppositories, various carriers conventionally known in this field can be employed. Examples include polyethylene glycol, cacao butter, higher alcohols and esters thereof, gelatin and semi-synthetic glyceride.
For formulation as injections, it is preferred that solutions or suspensions are sterilized and they are made isotonic with the blood. Solutions, emulsions or suspensions can be formed using any diluent conventionally used in this field. Examples include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and polyoxyethylene sorbitan esters of fatty acid. It is also possible to incorporate, in a pharmaceutical preparation, salt, glucose or glycerin in an amount sufficient for preparing an isotonic solution, or to add an ordinarily employed adjuvant for solubilization, buffer, soothing agent and/or the like.
If necessary a colourant, preservative, flavor, sweetener or other medicaments may be incorporated.
There is no particular limitation on the content of the compound incorporated as an effective ingredient in the above-described pharmaceutical preparation. It can be chosen suitably from a wide range. In general, it is desired to be contained in an amount of 1 to 70 wt. %, preferably 1 to 30 wt. % in the whole composition.
There is no particular limitation on the administering method of the above-described pharmaceutical preparation and it is determined depending on the dosage form or age, sex or other conditions of a patient to be administered or seriousness of the disease of the patient (human or other mammal). For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally. Injections are administered intravenously either singly or as a mixture with an ordinarily employed fluid replacement such as glucose or amino acid. If necessary, they are singly administered intramuscularly, subcutaneously, intracutaneously or intraperitoneally. A suppository is administered rectally.
Although the dose of the pharmaceutical composition differs with the conditions, age and weight of the patient, administration route or dosage form daily dose usually ranges from 2000 mg (preferably 100 mg) as the upper limit to 0.1 mg (preferably 1 mg, more preferably 10 mg) as the lower limit per adult. It can be administered once or in several portions a day according to the conditions.